Method and apparatus for patient temperature control employing administration of anti-shivering agents

ABSTRACT

Embodiments of the invention provide a system for temperature control of the human body. The system includes an indwelling catheter with a tip-mounted heat transfer element. The catheter is fluidically coupled to a console that provides a heated or cooled heat transfer working fluid to exchange heat with the heat transfer element, thereby heating or cooling blood. The heated or cooled blood then heats or cools the patient&#39;s body or a selected portion thereof. In particular, strategies for providing cooling while reducing shivering are disclosed, including administration of various drugs and drug combinations.

CONTINUING INFORMATION

[0001] This application is a continuation-in-part of U.S. Appl. Ser.Nos.: 09/650,940, entitled “SELECTIVE ORGAN HYPOTHERMIA METHOD ANDAPPARATUS,” filed on Aug. 30, 2000; Ser. No. 09/785,243, entitled“CIRCULATING FLUID HYPOTHERMIA METHOD AND APPARATUS,” filed on Feb. 16,2001; Ser. No. 09/566,531, entitled “METHOD OF MAKING SELECTIVE ORGANCOOLING CATHETER,” filed on May 8, 2000; Ser. No. 09/757,124, entitled“INFLATABLE CATHETER FOR SELECTIVE ORGAN HEATING AND COOLING AND METHODOF USING THE SAME,” filed on Jan. 8, 2001; Ser. No. 09/714,749, entitled“METHOD FOR LOW TEMPERATURE THROMBOLYSIS AND LOW TEMPERATURETHROMBOLYTIC AGENT WITH SELECTIVE ORGAN TEMPERATURE CONTROL,” filed onNov. 16, 2000; Ser. No. 09/621,051, entitled “METHOD AND DEVICE FORAPPLICATIONS OF SELECTIVE ORGAN COOLING,” filed on Jul. 21, 2000; Ser.No. 09/800,159, entitled “METHOD AND APPARATUS FOR LOCATION ANDTEMPERATURE SPECIFIC DRUG ACTION SUCH AS THROMBOLYSIS,” filed on Mar. 6,2001; Ser. No. 09/292,532, entitled “ISOLATED SELECTIVE ORGAN COOLINGMETHOD AND APPARATUS,” filed on Apr. 15, 1999; Ser. No. 09/379,295,entitled “METHOD OF MANUFACTURING A HEAT TRANSFER ELEMENT FOR IN VIVOCOOLING,” filed on Aug. 23, 1999; Ser. No. 09/885,655, entitled“INFLATABLE HEAT TRANSFER APPARATUS,” filed on Jun. 20, 2001; Ser. No.09/246,788, entitled “METHOD AND DEVICE FOR APPLICATIONS OF SELECTIVEORGAN COOLING,” filed on Mar. 28, 2001; Ser. No. 09/797,028, entitled“SELECTIVE ORGAN COOLING CATHETER WITH GUIDEWIRE APPARATUS ANDTEMPERATURE-MONITORING DEVICE,” filed on Feb. 27, 2001; Ser. No.09/607,799, entitled “SELECTIVE ORGAN COOLING APPARATUS AND METHOD,”filed on Jun. 30, 2000; Ser. No. 09/519,022, entitled “LUMEN DESIGN FORCATHETER,” filed on Mar. 3, 2000; 10/082,964, entitled “METHOD FORDETERMINING THE EFFECTIVE THERMAL MASS OF A BODY OR ORGAN USING ACOOLING CATHETER,” filed on Feb. 25, 2002; Ser. No. 09/539,932, entitled“MEDICAL PROCEDURE,” filed on Mar. 31, 2000; Ser. No. 09/658,950,entitled “MEDICAL PROCEDURE,” filed on Sep. 11, 2000; Ser. No.09/373,112, entitled “PATIENT TEMPERATURE REGULATION METHOD ANDAPPARATUS,” filed on Aug. 11, 1999; 10/007,545, entitled “CIRCULATIONSET FOR TEMPERATURE-CONTROLLED CATHETER AND METHOD OF USING THE SAME,”filed on Nov. 6, 2001; 10/005,416, entitled “FEVER REGULATION METHOD ANDAPPARATUS,” filed on Nov. 7, 2001; 10/117,733, entitled “METHOD OFMANUFACTURING A HEAT TRANSFER ELEMENT FOR IN VIVO COOLING,” filed onApr. 4, 2002; and is a conversion of U.S. Patent Application SerialNos.: 60/311,589, entitled “OPTIMAL REWARMING STRATEGIES,” filed on Aug.9, 2001; No. 60/312,409, entitled “CONTROLLING THE APPLICATION OFHYPOTHERMIA,” filed on Aug. 15, 2001; No. 60/316,057, entitled“CONTROLLING HYPOTHERMIA,” filed on Aug. 29, 2001; No. 60/316,922,entitled “NOVEL ANTISHIVER DRUGS AND REGIMENS,” filed on Aug. 31, 2001;No. 60/322,945, entitled “NOVEL ANTISHIVER DRUGS AND REGIMENS,” filed onSep. 14, 2001; No. 60/328,259, entitled “SINGLE OPERATOR EXCHANGECOAXIALLY COOLING CATHETER,” filed on Oct. 9, 2001; and No. 60/328,320,entitled “TEMPERATURE PROJECTION METHOD IN A CATHETER MOUNTEDTEMPERATURE SENSOR,” filed on Oct. 9, 2001; all of the above areincorporated by reference herein in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates generally to the lowering, raising,and control of the temperature of the human body. More particularly, theinvention relates to a method and intravascular apparatus forcontrolling the temperature of the human body.

BACKGROUND

[0003] Background Information—Organs in the human body, such as thebrain, kidney and heart, are maintained at a constant temperature ofapproximately 37° C. Hypothermia can be clinically defined as a corebody temperature of 35° C. or less. Hypothermia is sometimescharacterized further according to its severity. A body core temperaturein the range of 33° C to 35° C. is described as mild hypothermia. A bodytemperature of 28° C. to 32° C. is described as moderate hypothermia. Abody core temperature in the range of 24° C. to 28° C. is described assevere hypothermia.

[0004] Hypothermia is uniquely effective in reducing ischemia. Forexample, it is effective in reducing brain injury caused by a variety ofneurological insults and may eventually play an important role inemergency brain resuscitation. Experimental evidence has demonstratedthat cerebral cooling improves outcome after global ischemia, focalischemia, or traumatic brain injury. For this reason, hypothermia may beinduced in order to reduce the effect of certain bodily injuries to thebrain as well as ischemic injuries to other organs.

SUMMARY OF THE INVENTION

[0005] The apparatus of the present invention can include a heattransfer element which can be used to apply cooling to the blood flowingin a vessel. The heat transfer element, by way of example only,comprises first and second elongated, articulated segments, each segmenthaving a turbulence-inducing exterior surface. A flexible joint canconnect the first and second elongated segments. An inner coaxial lumenmay be disposed within the first and second elongated segments and iscapable of transporting a working fluid to a distal end of the firstelongated segment. In addition, the first and second elongated segmentsmay have a turbulence-inducing interior surface for inducing turbulencewithin the pressurized working fluid. The turbulence-inducing exteriorsurface may be adapted to induce turbulence within a free stream ofblood flow when placed within an artery or vein. The turbulence-inducingexterior surface may be adapted to induce a turbulence intensity greaterthan 0.05 within a free stream blood flow. In one embodiment, theflexible joint comprises a bellows section which also allows for axialcompression of the heat transfer element.

[0006] In an embodiment, the turbulence-inducing exterior surfaces ofthe heat transfer element comprise one or more helical ridges. Adjacentsegments of the heat transfer element can be oppositely spiraled toincrease turbulence. For instance, the first elongated heat transfersegment may comprise one or more helical ridges having acounter-clockwise twist, while the second elongated heat transfersegment comprises one or more helical ridges having a clockwise twist.Alternatively, of course, the first elongated heat transfer segment maycomprise one or more clockwise helical ridges, and the second elongatedheat transfer segment may comprise one or more counter-clockwise helicalridges. The first and second elongated, articulated segments may beformed from highly conductive materials.

[0007] The heat transfer device may also have a coaxial supply catheterwith an inner catheter lumen coupled to the inner coaxial lumen withinthe first and second elongated heat transfer segments. A working fluidsupply configured to dispense the pressurized working fluid may becoupled to the inner catheter lumen. The working fluid supply may beconfigured to produce the pressurized working fluid at a temperature ofabout 0° C. and at a pressure below about 5 atmospheres of pressure. Theworking fluid may be isolyte, saline, D5W, etc.

[0008] In yet another alternative embodiment, the heat transfer devicemay have three or more elongated, articulated, heat transfer segmentshaving a turbulence-inducing exterior surface, with additional flexiblejoints connecting the additional elongated heat transfer segments. Inone such embodiment, by way of example, the first and third elongatedheat transfer segments may comprise clockwise helical ridges, and thesecond elongated heat transfer segment may comprise one or morecounter-clockwise helical ridges. Alternatively, of course, the firstand third elongated heat transfer segments may comprisecounter-clockwise helical ridges, and the second elongated heat transfersegment may comprise one or more clockwise helical ridges.

[0009] The turbulence-inducing exterior surface of the heat transferelement may optionally include a surface coating or treatment to inhibitclot formation.

[0010] The present invention also envisions a method of cooling the bodywhich comprises inserting a flexible, conductive cooling element intothe inferior vena cava from a distal location, and providing a means ofwarming the body to prevent shivering by means of a cooling blanket. Themethod further includes circulating a working fluid through theflexible, conductive cooling element in order to lower the temperatureof the body. The flexible, conductive heat transfer element absorbs morethan about 25, 50 or 75 Watts of heat.

[0011] The method may also comprise inducing turbulence within the freestream blood flow within an artery or vein. In one embodiment, themethod includes the step of inducing blood turbulence with a turbulenceintensity greater than about 0.05 within the vascular system. Thecirculating may comprise inducing mixing flow of the working fluidthrough the flexible, conductive heat transfer element. The pressure ofthe working fluid may be maintained below about 5 atmospheres ofpressure.

[0012] The cooling or warming may comprise circulating a working fluidin through an inner lumen in the catheter and out through an outer,coaxial lumen. In one embodiment, the working fluid remains a liquidthroughout the cycle. The working fluid may be aqueous.

[0013] The present invention also envisions a cooling or warmingcatheter comprising a catheter shaft having first and second lumenstherein. The catheter also comprises a cooling or warming tip adapted totransfer heat to or from a working fluid circulated in through the firstlumen and out through the second lumen, and turbulence-inducingstructures on the tip capable of inducing free stream turbulence whenthe tip is inserted into a blood vessel. The tip may be adapted toinduce turbulence within the working fluid. The catheter is capable ofremoving at least about 25 Watts of heat from an organ when insertedinto a vessel supplying that organ, while cooling the tip with a workingfluid that remains a liquid in the catheter. Alternatively, the catheteris capable of removing at least about 50 or 75 Watts of heat from anorgan when inserted into a vessel supplying that organ, while coolingthe tip with an aqueous working fluid.

[0014] In another embodiment, a cooling or warming catheter may comprisea catheter shaft having first and second lumens therein, a cooling orwarming tip adapted to transfer heat to or from a working fluidcirculated in through the first lumen and out through the second lumen,and turbulence-inducing structures on the tip capable of inducingturbulence when the tip is inserted into a blood vessel.

[0015] The present invention may also provide a temperature controlapparatus comprising a flexible catheter which can be inserted throughthe vascular system of a patient to an artery or vein, with aninflatable balloon heat exchanger near the distal end of the catheter.The present invention also encompasses a method for using such a deviceto perform cooling, heating, or temperature management. After placementin a vessel, an embodiment of the invention includes an apparatus wherethe heat exchanger balloon is inflated by pressurization with a workingfluid, such as saline, isolyte, D5W, or other similar fluids, orcombinations of these, via a supply lumen in the catheter. The heatexchanger balloon has one or more blood passageways passing through it,from a proximal aspect of the balloon to a distal aspect of the balloon.When the heat exchanger balloon is inflated to contact the wall of theartery in which it is placed, each of the blood passageways comprises atube having an inlet in one face of the heat exchanger balloon and anoutlet in another face of the heat exchanger balloon, thereby allowingblood to continue flowing through the artery after inflation of theballoon. The blood passageway tubes can be constructed of a materialhaving a relatively high thermal conductivity, such as a thin metallizedpolymer, such as a film with one or more metallized surfaces.Alternatively, the blood passageway tubes can be constructed of ametal-loaded polymer film. Further, the entire heat exchanger ballooncan be constructed of such a material, in order to maximize the coolingcapacity of the heat exchanger.

[0016] After inflation of the heat exchanger balloon, the salinesolution, which is chilled by an external chiller, continues circulatingthrough the interior of the heat exchanger balloon, around the bloodpassageway tubes, and back out of the balloon through a return lumen inthe catheter. This cools the blood passageway tubes, which in turn coolthe blood flowing through them. This cooled blood then flows through theselected organ and cools the organ.

[0017] The device can also incorporate a lumen for a guidewire,facilitating the navigation of the catheter through the vascular systemof the patient.

[0018] In one aspect, the invention is directed to a catheter system tochange the temperature of blood by heat transfer to or from a workingfluid. The system includes an inflatable inlet lumen and outlet lumen.The outlet lumen is coupled to the inlet lumen so as to transfer workingfluid between the two. The outlet lumen has a structure when inflated toinduce turbulence in the blood and/or in the working fluid.

[0019] Variations of the system may include one or more of thefollowing. The inlet lumen and the outlet lumen may be made of aflexible material such as latex rubber. The outlet lumen may have astructure to induce turbulence in the working fluid when inflated, suchas a helical shape which may be tapered in a segmented or non-segmentedmanner. The radii of the inlet and outlet lumens may decrease in adistal direction such that the inlet and outlet lumens are tapered wheninflated. A wire may be disposed in the inlet or outlet lumens toprovide shape and strength when deflated.

[0020] The thickness of the outlet lumen, when inflated, may be lessthan about ½ mil. The length of the inlet lumen may be between about 5and 30 centimeters. If the outlet lumen has a helical shape, thediameter of the helix may be less than about 8 millimeters wheninflated. The outer diameter of the helix of the outlet lumen, wheninflated, may be between about 2 millimeters and 8 millimeters and maytaper to between about 1 millimeter and 2 millimeters. In segmentedembodiments, a length of a segment may be between about 1 centimeter and10 centimeters. The radii of the inlet and outlet lumens when inflatedmay be between about 0.5 millimeters and 2 millimeters.

[0021] The outlet lumen may further include at least one surface featureand/or interior feature, the surface feature inducing turbulence in thefluid adjacent the outlet lumen and the interior feature inducingturbulence in the working fluid. The surface feature may include one ormore helical turns or spirals formed in the outlet lumen. Adjacent turnsmay employ opposite helicity. Alternatively or in combination, thesurface feature may be a series of staggered protrusions formed in theoutlet lumen.

[0022] The turbulence-inducing outlet lumen may be adapted to induceturbulence when inflated within a free stream of blood when placedwithin an artery. The turbulence intensity may be greater than about0.05. The turbulence-inducing outlet lumen may be adapted to induceturbulence when inflated throughout the period of the cardiac cycle whenplaced within an artery or during at least 20% of the period.

[0023] The system may further include a coaxial supply catheter havingan inner catheter lumen coupled to the inlet lumen and a working fluidsupply configured to dispense the working fluid and having an outputcoupled to the inner catheter lumen. The working fluid supply may beconfigured to produce a pressurized working fluid at a temperature ofbetween about −3° C. and 36° C. and at a pressure below about 5atmospheres of pressure. Higher temperatures may be employed if bloodheating is desired.

[0024] The turbulence-inducing outlet lumen may include a surfacecoating or treatment such as heparin to inhibit clot formation. A stentmay be coupled to the distal end of the inlet lumen. The system may beemployed to cool or heat volumes of tissue rather than blood.

[0025] In embodiments employing a tapered helical outlet lumen, thetaper of the outlet lumen allows the outlet lumen to be placed in anartery having a radius less than the first radius. The outlet lumen maybe tapered in segments. The segments may be separated by joints, thejoints having a radius less than that of either adjacent segment.

[0026] In another aspect, the invention is directed to a method ofchanging the temperature of blood by heat transfer. The method includesinserting an inflatable heat transfer element into an artery or vein andinflating the same by delivering a working fluid to its interior. Thetemperature of the working fluid is generally different from that of theblood. The method further includes inducing turbulence in the workingfluid by passing the working fluid through a turbulence-inducing path,such that turbulence is induced in a substantial portion of a freestream of blood. The inflatable heat transfer element may have aturbulence-inducing structure when inflated.

[0027] In another aspect, the invention is directed towards a method oftreating the brain which includes inserting a flexible heat transferelement into an artery from a distal location and circulating a workingfluid through the flexible heat transfer element to inflate the same andto selectively modify the temperature of an organ without significantlymodifying the temperature of the entire body. The flexible, conductiveheat transfer element preferably absorbs more than about 25, 50 or 75watts of heat. The artery may be the common carotid or a combination ofthe common carotid and the internal carotid.

[0028] In another aspect, the invention is directed towards a method forselectively cooling an organ in the body of a patient which includesintroducing a catheter into a blood vessel supplying the organ, thecatheter having a diameter of 5 mm or less, inducing free streamturbulence in blood flowing over the catheter, and cooling the catheterto remove heat from the blood to cool the organ without substantiallycooling the entire body. In one embodiment, the cooling removes at leastabout 75 watts of heat from the blood. In another embodiment, thecooling removes at least about 100 watts of heat from the blood. Theorgan being cooled may be the human brain.

[0029] The circulating may further include passing the working fluid inthrough an inlet lumen and out through an outlet, coaxial lumen. Theworking fluid may be a liquid at or well below its boiling point, andfurthermore may be aqueous.

[0030] Advantages of the invention include one or more of the following.The design criteria described above for the heat transfer element: smalldiameter when deflated, large diameter when inflated, high flexibility,and enhanced heat transfer rate through increases in the surface of theheat transfer element and the creation of turbulent flow, facilitatecreation of a heat transfer element which successfully achievesselective organ cooling or heating. Because the blood is cooledintravascularly, or in situ, problems associated with externalcirculation of the blood are eliminated. Also, only a single punctureand arterial vessel cannulation are required which may be performed atan easily accessible artery such as the femoral, subclavian, or brachialarteries. By eliminating the use of a cold perfusate, problemsassociated with excessive fluid accumulation are avoided. In addition,rapid cooling to a precise temperature may be achieved. Further,treatment of a patient is not cumbersome and the patient may easilyreceive continued care during the heat transfer process. The device andmethod may be easily combined with other devices and techniques toprovide aggressive multiple therapies. Other advantages will

[0031] The present invention involves a device for heating or cooling asurrounding fluid in a blood vessel that addresses and solves theproblems discussed above. The device includes an elongated catheterbody, a heat transfer element located at a distal portion of thecatheter body and including an interior, an elongated supply lumenadapted to deliver a working fluid to the interior of the heat transferelement and having a hydraulic diameter, an elongated return lumenadapted to return a working fluid from the interior of the heat transferelement and having a hydraulic diameter, and wherein the ratio of thehydraulic diameter of the return lumen to the hydraulic diameter of thesupply lumen is substantially equal to 0.75.

[0032] Implementations of the above aspect of the invention may includeone or more of the following. The supply lumen may be disposedsubstantially within the return lumen. One of the supply lumen andreturn lumen may have a cross-sectional shape that is substantiallyluniform. One of the supply lumen and the return lumen has across-sectional shape that is substantially annular. The supply lumenhas a general cross-sectional shape and the return lumen has a generalcross-sectional shape different from the general cross-sectional shapeof the supply lumen. The catheter assembly includes an integratedelongated bi-lumen member having a first lumen adapted to receive aguide wire and a second lumen comprising either the supply lumen or thereturn lumen. The bi-lumen member has a cross-sectional shape that issubstantially in the shape of a figure eight. The first lumen has across-sectional shape that is substantially circular and the secondlumen has a cross-sectional shape that is substantially annular. Theheat transfer element includes means for inducing mixing in asurrounding fluid. The device further includes means for inducing walljets or means for further enhancing mixing of the working fluid toeffect further heat transfer between the heat transfer element andworking fluid. The heat transfer element includes an interior distalportion and the supply lumen includes first means for delivering workingfluid to the interior distal portion of the heat transfer element andsecond means for delivering working fluid to the interior of the heattransfer element at one or more points point proximal to the distalportion of the heat transfer element.

[0033] Another of the invention involves a catheter assembly capable ofinsertion into a selected blood vessel in the vascular system of apatient. The catheter assembly includes an elongated catheter bodyincluding an operative element having an interior at a distal portion ofthe catheter body, an elongated supply lumen adapted to deliver aworking fluid to the interior of the distal portion and having ahydraulic diameter, an elongated return lumen adapted to return aworking fluid from the interior of the operative element and having ahydraulic diameter, and wherein the ratio of the hydraulic diameter ofthe return lumen to the hydraulic diameter of the supply lumen beingsubstantially equal to 0.75.

[0034] Any of the implementations described above with respect to oneaspect of the invention may also apply to other aspects of theinvention. Further, implementations of the invention may include one ormore of the following. The operative element may include a heat transferelement adapted to transfer heat to or from the working fluid. The heattransfer element may include means for inducing mixing in a surroundingfluid. The operative element may include a catheter balloon adapted tobe inflated with the working fluid.

[0035] Another aspect of the invention involves a device for heating orcooling a surrounding fluid in a vascular blood vessel. The deviceincludes an elongated catheter body, a heat transfer element located ata distal portion of the catheter body and including an interior, anintegrated elongated bi-lumen member located within the catheter bodyand including a first lumen adapted to receive a guide wire and a secondlumen, the second lumen comprising either a supply lumen to deliver aworking fluid to an interior of the heat transfer element or a returnlumen to return a working fluid from the interior of the heat transferelement, and a third lumen comprising either a supply lumen to deliver aworking fluid to an interior of the heat transfer element or a returnlumen to return a working fluid from the interior of the heat transferelement.

[0036] Implementations of the invention may include one or more of thefollowing. The catheter body includes an internal wall and theintegrated bi-lumen member includes an exterior wall, and the thirdlumen is substantially defined by the internal wall of the catheter bodyand the exterior wall of the bi-lumen member. Both the catheter body andthe bi-lumen member are extruded. The bi-lumen member is disposedsubstantially within the third lumen. The second lumen has across-sectional shape that is substantially luniform. The third lumenhas a cross-sectional shape that is substantially annular. The secondlumen has a general cross-sectional shape and the third lumen has ageneral cross-sectional shape different from the general cross-sectionalshape of the second lumen. The bi-lumen member has a cross-sectionalshape that is substantially in the shape of a figure eight. The firstlumen has a cross-sectional shape that is substantially circular and thesecond lumen has a cross-sectional shape that is substantially luniform.The heat transfer element includes means for inducing mixing in asurrounding fluid. The device further includes means for inducing walljets or means for further enhancing mixing of the working fluid toeffect further heat transfer between the heat transfer element andworking fluid. The heat transfer element includes an interior distalportion and the supply lumen includes first means for delivering workingfluid to the interior distal portion of the heat transfer element andsecond means for delivering working fluid to the interior of the heattransfer element at one or more points point proximal to the distalportion of the heat transfer element.

[0037] Another aspect of the present invention involves a catheterassembly capable of insertion into a selected blood vessel in thevascular system of a patient. The catheter assembly includes anelongated catheter body including an operative element having aninterior at a distal portion of the catheter body, an integratedelongated bi-lumen member located within the catheter body and includinga first lumen adapted to receive a guide wire and a second lumen, thesecond lumen comprising either a supply lumen to deliver a working fluidto the interior of the operative element or a return lumen to return aworking fluid from the interior of the operative element, and a thirdlumen within the catheter body and comprising either a supply lumen todeliver a working fluid to an interior of the operative element or areturn lumen to return a working fluid from the interior of theoperative element.

[0038] Another aspect of the invention involves a method ofmanufacturing a catheter assembly for heating or cooling a surroundingfluid in a blood vessel. The method involves extruding an elongatedcatheter body; locating a heat transfer element including an interior ata distal portion of the catheter body; extruding an integrated elongatedbi-lumen member including a first lumen adapted to receive a guide wireand a second lumen, the second lumen comprising either a supply lumen todeliver a working fluid to an interior of the heat transfer element or areturn lumen to return a working fluid from the interior of the heattransfer element; and providing the integrated bi-lumen membersubstantially within the elongated catheter body so that a third lumenis formed, the third lumen comprising either a supply lumen to deliver aworking fluid to an interior of the heat transfer element or a returnlumen to return a working fluid from the interior of the heat transferelement.

[0039] Implementations of the invention may include one or more of thefollowing. The second lumen has a hydraulic diameter and the third lumenhas a hydraulic diameter, and the ratio of the hydraulic diameter of thesecond lumen to the hydraulic diameter of the third lumen issubstantially equal to 0.75. The step of providing the integratedbi-lumen member substantially within the elongated catheter bodyincludes simultaneously extruding the integrated bi-lumen membersubstantially within the elongated catheter body.

[0040] Another aspect of the present invention involves a method ofmanufacturing a catheter assembly. The method includes extruding anelongated catheter body; locating an operative element including aninterior at a distal portion of the catheter body; extruding anintegrated elongated bi-lumen member including a first lumen adapted toreceive a guide wire and a second lumen, the second lumen comprisingeither a supply lumen to deliver a working fluid to an interior of theoperative element or a return lumen to return a working fluid from theinterior of the operative element; and providing the integrated bi-lumenmember substantially within the elongated catheter body so that a thirdlumen is formed, the third lumen comprising either a supply lumen todeliver a working fluid to an interior of the operative element or areturn lumen to return a working fluid from the interior of theoperative element.

[0041] Another aspect of the present invention involves a device forheating or cooling a surrounding fluid in a blood vessel. The deviceincludes an elongated catheter body, a heat transfer element located ata distal portion of the catheter body and including an interior distalportion and an interior portion defining at least a first heat transfersegment and a second heat transfer segment, and at least one elongatedsupply lumen located within the catheter body, the at least oneelongated supply lumen including first means for delivering workingfluid to the interior distal portion of the first heat transfer segmentand second means for delivering working fluid to the interior portion ofthe second heat transfer segment.

[0042] In an implementation of the invention, the second working fluiddelivering means is adapted to deliver working fluid to the interiorportion of the heat transfer element near a midpoint of the heattransfer element.

[0043] Another aspect of the present invention involves a device forheating or cooling a surrounding fluid in a blood vessel. The deviceincludes an elongated catheter body, a heat transfer element located ata distal portion of the catheter body and including an interior distalportion and an interior portion, and at least one elongated supply lumenlocated within the catheter body, the at least one elongated supplylumen including first means for delivering working fluid to the interiordistal portion of the heat transfer element and second means fordelivering working fluid to the interior portion of the heat transferelement at one or more points proximal to the distal portion of the heattransfer element.

[0044] In an implementation of the invention, the second working fluiddelivering means is adapted to deliver working fluid to the interiorportion of the heat transfer element near a midpoint of the heattransfer element.

[0045] Another aspect of the present invention involves a device forheating or cooling a surrounding fluid in a blood vessel. The deviceincludes an elongated catheter body, a heat transfer element located ata distal portion of the catheter body and including an interior distalportion and an interior portion defining at least a first heat transfersegment and a second heat transfer segment, a first elongated supplylumen located within the catheter body and terminating at the interiordistal portion of the heat transfer element into first means fordelivering working fluid to the interior distal portion of the heattransfer element, and a second elongated supply lumen located within thecatheter body and terminating at a point proximal to the distal portionof the heat transfer element into second means for delivering workingfluid to the interior portion of the heat transfer element at a pointproximal to the distal portion of the heat transfer element.

[0046] In an implementation of the invention, the second working fluiddelivering means is adapted to deliver working fluid to the interiorportion of the heat transfer element near a midpoint of the heattransfer element.

[0047] Another aspect of the present invention involves a device forheating or cooling a surrounding fluid in a blood vessel. The deviceincludes an elongated catheter body, a heat transfer element located ata distal portion of the catheter body and including an interior distalportion and an interior portion defining at least a first heat transfersegment interior portion and a second heat transfer segment interiorportion, a first elongated supply lumen located within the catheter bodyand terminating at the interior distal portion of the first heattransfer segment into first means for delivering working fluid to theinterior of the first heat transfer segment, and a second elongatedsupply lumen located within the catheter body and terminating at a pointproximal to the distal portion of the heat transfer element into secondmeans for delivering working fluid to the interior portion of the secondheat transfer segment.

[0048] In an implementation of the invention, the second working fluiddelivering means is adapted to deliver working fluid to the interiorportion of the heat transfer element near a midpoint of the heattransfer element.

[0049] Another aspect of the present invention involves a device forheating or cooling a surrounding fluid in a blood vessel. The deviceincludes an elongated catheter body, a heat transfer element located ata distal portion of the catheter body and including an interior portionadapted to induce mixing of a working fluid to effect heat transferbetween the heat transfer element and working fluid, the heat transferelement including at least a first heat transfer segment, a second heattransfer segment, and an intermediate segment between the first heattransfer segment and the second heat transfer segment, an elongatedsupply lumen member located within the catheter body and adapted todeliver the working fluid to the interior of the heat transfer element,the supply lumen member including a circular outer surface, an elongatedreturn lumen defined in part by the outer surface of the supply lumenmember and the interior portion of the heat transfer element and adaptedto return the working fluid from the interior of the heat transferelement, and wherein the distance between the interior portion of theheat transfer element and the outer surface of the supply lumen memberadjacent the intermediate segment is less than the distance between theinterior portion of the heat transfer element and the outer surface ofthe supply lumen member adjacent the first heat transfer segment.

[0050] Implementations of the invention may include one or more of thefollowing. The distance between the interior portion of the heattransfer element and the outer surface of the supply lumen memberadjacent the intermediate segment is such that the characteristic flowresulting from a flow of working fluid is at least of a transitionalnature. The intermediate segment includes an interior diameter that isless than the interior diameter of the first heat transfer segment orthe second heat transfer segment. The supply lumen member includes anouter diameter adjacent the intermediate segment that is greater thanits outer diameter adjacent the first heat transfer segment or thesecond heat transfer segment. The supply lumen member comprises amultiple-lumen member. The supply lumen member includes a supply lumenhaving a hydraulic diameter and the return lumen has a hydraulicdiameter substantially equal to 0.75 the hydraulic diameter of thesupply lumen. The intermediate segment includes a flexible bellowsjoint.

[0051] Another aspect of the present invention involves a device forheating or cooling a surrounding fluid in a blood vessel. The deviceincludes an elongated catheter body, a heat transfer element located ata distal portion of the catheter body and including an interior portionadapted to induce mixing of a working fluid to effect heat transferbetween the heat transfer element and working fluid, an elongated supplylumen member located within the catheter body and adapted to deliver theworking fluid to the interior of the heat transfer element, an elongatedreturn lumen member located within the catheter body and adapted toreturn the working fluid from the interior of the heat transfer element,and means located within the heat transfer element for further enhancingmixing of the working fluid to effect further heat transfer between theheat transfer element and working fluid.

[0052] Implementations of the invention may include one or more of thefollowing. The supply lumen member comprises a multiple-lumen memberhaving a circular outer surface. The supply lumen member includes asupply lumen having a hydraulic diameter and the return lumen has ahydraulic diameter substantially equal to 0.75 of the hydraulic diameterof the supply lumen.

[0053] Another aspect of the present invention involves a device forheating or cooling a surrounding fluid in a blood vessel. The deviceincludes an elongated catheter body, a heat transfer element located ata distal portion of the catheter body and including an interior portionadapted to induce mixing of a working fluid to effect heat transferbetween the heat transfer element and working fluid, an elongated supplylumen member located within the catheter body and adapted to deliver theworking fluid to the interior of the heat transfer element, an elongatedreturn lumen member located within the catheter body and adapted toreturn the working fluid from the interior of the heat transfer element,and a mixing-enhancing mechanism located within the heat transferelement and adapted to further mix the working fluid to effect furtherheat transfer between the heat transfer element and working fluid.

[0054] Implementations of the invention may include one or more of thefollowing. The supply lumen member comprises a multiple-lumen memberhaving a circular outer surface. The supply lumen member includes asupply lumen having a hydraulic diameter and the return lumen has ahydraulic diameter substantially equal to the hydraulic diameter of thesupply lumen. A fourteenth aspect of the present invention involves amethod of heating or cooling a surrounding fluid in a blood vessel. Themethod includes providing a device for heating or cooling a surroundingfluid in a blood vessel within the blood stream of a blood vessel, thedevice including an elongated catheter body, a heat transfer elementlocated at a distal portion of the catheter body and including aninterior portion adapted to induce mixing of a working fluid to effectheat transfer between the heat transfer element and working fluid, anelongated supply lumen member located within the catheter body andadapted to deliver the working fluid to the interior of the heattransfer element, an elongated return lumen member located within thecatheter body and adapted to return the working fluid from the interiorof the heat transfer element, and a mixing-enhancing mechanism locatedwithin the heat transfer element and adapted to further mix the workingfluid to effect further heat transfer between the heat transfer elementand working fluid; causing a working fluid to flow to and along theinterior portion of the heat transfer element of the device using thesupply lumen and return lumen; facilitating the transfer of heat betweenthe working fluid and the heat transfer element by effecting mixing ofthe working fluid with the interior portion adapted to induce mixing ofa working fluid; facilitating additional transfer of heat between theworking fluid and the heat transfer element by effecting further mixingof the working fluid with the interior portion with the mixing-enhancingmechanism; causing heat to be transferred between the blood stream andthe heat transfer element by the heat transferred between the heattransfer element and working fluid.

BRIEF DESCRIPTION OF THE DRAWINGS

[0055] The novel features of this invention, as well as the inventionitself, will be best understood fr om the attached drawings, taken alongwith the following description, in which similar reference charactersrefer to similar parts, and in which:

[0056]FIG. 1 is a schematic representation of the heat transfer elementbeing used in an embodiment within the superior vena cava;

[0057]FIG. 2 is a graph showing preferential cooling of the high floworgans of the body under a hypothermic therapy; and

[0058]FIG. 3 is a graph illustrating the velocity of steady stateturbulent flow as a function of time;

[0059]FIG. 4 is a graph showing the velocity of the blood flow within anartery as a function of time;

[0060]FIG. 5 is a graph illustrating the velocity of steady stateturbulent flow under pulsatile conditions as a function of time, similarto arterial blood flow;

[0061]FIG. 6 is an elevation view of a turbulence inducing heat transferelement within an artery;

[0062]FIG. 7 is a velocity profile diagram showing a typical steadystate Poiseuillean flow driven by a constant pressure gradient;

[0063]FIG. 8 is a velocity profile diagram showing blood flow velocitywithin an artery, averaged over the duration of the cardiac pulse;

[0064]FIG. 9 is a velocity profile diagram showing blood flow velocitywithin an artery, averaged over the duration of the cardiac pulse, afterinsertion of a smooth heat transfer element within the artery;

[0065]FIG. 10 is a schematic diagram of a heat transfer elementaccording to an embodiment of the invention.

[0066]FIG. 11 is a graph showing the relationship between the Nusseltnumber (Nu) and the Reynolds number (Re) for air flowing through a longheated pipe at uniform wall temperature.

[0067]FIG. 12 is an elevation view of one embodiment of a heat transferelement according to the invention;

[0068]FIG. 13 is a longitudinal section view of the heat transferelement of FIG. 1;

[0069]FIG. 14 is a transverse section view of the heat transfer elementof FIG. 1;

[0070]FIG. 15 is a perspective view of the heat transfer element of FIG.1 in use within a blood vessel;

[0071]FIG. 16 is a perspective view of another embodiment of a heattransfer element according to the invention, with aligned longitudinalridges on adjacent segments;

[0072]FIG. 17 is a perspective view of another embodiment of a heattransfer element according to the invention, with somewhat offsetlongitudinal ridges on adjacent segments; and

[0073]FIG. 18 is a transverse section view of the heat transfer elementof FIG. 16 or FIG. 17.

[0074]FIG. 19 is a cut-away perspective view of an alternativeembodiment of a heat transfer element according to the invention;

[0075]FIG. 20 is a transverse section view of the heat transfer elementof FIG. 5;

[0076]FIG. 21 is a front sectional view of a further embodiment of acatheter employing a heat transfer element according to the principlesof the invention further employing a side-by-side lumen arrangementconstructed in accordance with an embodiment of the invention;

[0077]FIG. 22 is a cross-sectional view of the catheter of FIG. 21 takenalong line 22-22 of FIG. 21;

[0078]FIG. 23 is a front sectional view of a catheter employing a heattransfer element and lumen arrangement constructed in accordance with afurther embodiment of the invention;

[0079]FIG. 24 is a front sectional view of a catheter employing a heattransfer element and lumen arrangement constructed in accordance with astill further embodiment of the invention; and

[0080]FIG. 25 is a front sectional view of a another embodiment of acatheter employing a heat transfer element according to the principlesof the invention further employing a side-by-side lumen arrangementconstructed in accordance with another embodiment of the invention; and

[0081]FIG. 26 is a cross-sectional view of the heat transfer elementillustrated in FIG. 25 taken along line 26-26 of FIG. 25.

[0082]FIG. 27 is a side schematic view of an inflatableturbulence-inducing heat transfer element according to an embodiment ofthe invention, as the same is disposed within an artery.

[0083]FIG. 28 illustrates an inflatable turbulence-inducing heattransfer element according to an alternative embodiment of the inventionemploying a surface area enhancing taper and a turbulence-inducingshape.

[0084]FIG. 29 illustrates a tapered joint which may be employed in theembodiment of FIG. 23.

[0085]FIG. 30 illustrates a turbulence-inducing heat transfer elementaccording to a second alternative embodiment of the invention employinga surface area enhancing taper and turbulence-inducing surface features.

[0086]FIG. 31 illustrates a type of turbulence-inducing surface featurewhich may be employed in the heat transfer element of the embodiment ofFIG. 28. In FIG. 31 a spiral feature is shown.

[0087]FIG. 32 illustrates a heat transfer element according to analternative embodiment of the invention employing a surface areaenhancing taper.

[0088]FIG. 33 illustrates another type of turbulence-inducing surfacefeature which may be employed in the heat transfer element of theembodiment of FIG. 27. In FIG. 33, a series of staggered protrusions areshown.

[0089]FIG. 34 is a transverse cross-sectional view of the heat transferelement of the embodiment of FIG. 33.

[0090]FIG. 35 is a perspective view of the device of the presentinvention in place in a common carotid artery of a patient;

[0091]FIG. 36 is a perspective view of the device shown in FIG. 35, withadditional details of construction;

[0092]FIG. 37 is a transverse section view of the device shown in FIG.36, along the section line 3-3; and

[0093]FIG. 38 is a partial longitudinal section view of the device shownin FIG. 30, showing the flow path of the cooling fluid.

[0094]FIG. 39 is a schematic representation of the heat transfer elementbeing used in one embodiment to provide hypothermia to a patient bycausing total body cooling and then rewarming the body;

[0095]FIG. 40 is a schematic representation of the heat transfer elementbeing used in one embodiment to cool the brain of a patient and to warmthe blood returning from the brain in the jugular vein;

[0096]FIG. 41 is a schematic representation of the heat transfer elementbeing used in one embodiment to cool the brain of a patient, while awarm saline solution is infused to warm the blood returning from thebrain in the jugular vein; and

[0097]FIG. 42 is a schematic representation of one embodiment of anexternal warming device which can be used to warm the blood returningfrom an organ in a vein.

[0098]FIG. 43 is a schematic representation of the heat transfer elementbeing used in another embodiment to provide hypothermia to a patient bycausing total body cooling and then rewarming the body;

[0099]FIG. 44 is a flowchart showing an exemplary method of theinvention employing heating blankets and thermoregulatory drugs.

[0100]FIG. 45 shows a meperidine molecule FIG. 46 shows a morphinemolecule.

[0101]FIG. 47 shows a prodine (+) isomer molecule.

[0102]FIG. 48 shows a prodine (−) isomer molecule.

[0103]FIG. 49 shows a fentanyl molecule.

[0104]FIG. 50 shows a hydroxy allyl prodine (+) isomer molecule.

[0105]FIG. 51 shows a picenadol (+) isomermolecule.

[0106]FIG. 52 shows a picenadol (−) isomer molecule.

[0107]FIG. 53 shows a tramadol molecule.

[0108]FIG. 54 shows a nefopam molecule.

[0109]FIG. 55 is a schematic representation of the use of a heattransfer element to cool the body, according to an embodiment of theinvention.

[0110]FIG. 56 is a flowchart showing an exemplary method of theinvention.

[0111]FIG. 57 shows a catheter having a manifold constructed inaccordance with the present invention.

[0112]FIG. 58 is an enlarged sectional view of a fragmentary portion ofthe catheter shown in FIG. 57.

[0113]FIG. 59 is a perspective view of a heat transfer catheter systemincluding a circulation set constructed in accordance with an embodimentof the invention;

[0114]FIG. 60 is a cross-sectional view of an embodiment of a distalportion of a heat transfer catheter along with a side-elevational viewof an embodiment of a proximal portion of the catheter that may be usedwith the circulation set illustrated in FIG. 59;

[0115]FIG. 61 is a schematic view of a valve that may be employed in anembodiment of the present invention.

[0116]FIG. 62 is a schematic diagram of the circulation set illustratedin FIG. 48;

[0117]FIG. 63 is an exploded perspective view of an embodiment of adisposable heat exchanger that may be used in the circulation set of thepresent invention.

[0118]FIG. 64 is a cross sectional view of the heat exchangerillustrated in FIG. 52.

[0119]FIGS. 65 and 66 are perspective views of the manifold portions ofthe heat exchanger illustrated in FIG. 63.

[0120]FIG. 67 is a perspective view of a temperature and pressure sensorassembly constructed in accordance with an embodiment of the invention;

[0121]FIG. 68 is an exploded perspective view of the temperature andpressure sensor assembly illustrated in FIG. 67.

[0122]FIG. 69 is an exploded side-elevational view of the temperatureand pressure sensor assembly illustrated in FIG. 67.

[0123]FIG. 70 is an exploded perspective view of the temperature andpressure sensor assembly illustrated in FIG. 67, but from a differentvantage point from that of FIG. 68.

[0124]FIG. 71 is an exemplary graph of a pump motor speed versus timefor a pump of the circulation set illustrated in FIG. 59.

[0125]FIG. 72 is an exemplary graph of pressure versus pump motor speedfor a 10 F heat transfer catheter and a 14 F heat transfer catheter usedwith the circulation set illustrated in FIG. 59.

[0126]FIG. 73 is a schematic representation of layers constituting awall of the heat transfer element according to an embodiment of theinvention and formed by a method according to the invention;

[0127]FIG. 74 is a schematic representation of layers constituting awall of the heat transfer element according to a second embodiment ofthe invention and formed by a method according to the invention; and

[0128]FIG. 75 is an exploded schematic representation of layersconstituting a wall of the heat transfer element according to a thirdembodiment of the invention and formed by a method according to theinvention.

DETAILED DESCRIPTION

[0129] Overview

[0130] In the following description, the term “pressure communication”is used to describe a situation between two points in a flow or in astanding fluid. If pressure is applied at one point, the second pointwill eventually feel effects of the pressure if the two points are inpressure communication. Any number of valves or elements may be disposedbetween the two points, and the two points may still be in pressurecommunication if the above test is met. For example, for a standingfluid in a pipe, any number of pipe fittings may be disposed between twopipes and, so long as an open path is maintained, points in therespective pipes may still be in pressure communication.

[0131] A one or two-step process and a one or two-piece device may beemployed to intravascularly lower the temperature of a body in order toinduce therapeutic hypothermia. A cooling element may be placed in ahigh-flow vein such as the vena cavae to absorb heat from the bloodflowing into the heart. This transfer of heat causes a cooling of theblood flowing through the heart and thus throughout the vasculature.Such a method and device may therapeutically be used to induce anartificial state of hypothermia.

[0132] A heat transfer element that systemically cools blood should becapable of providing the necessary heat transfer rate to produce thedesired cooling effect throughout the vasculature. This may be up to orgreater than 300 watts, and is at least partially dependent on the massof the patient and the rate of blood flow. Surface features may beemployed on the heat transfer element to enhance the heat transfer rate.The surface features and other components of the heat transfer elementare described in more detail below.

[0133] One problem with hypothermia as a therapy is that the patient'sthermoregulatory defenses initiate, attempting to defeat thehypothermia. Methods and devices may be used to lessen thethermoregulatory response. For example, a heating blanket may cover thepatient. In this way, the patient may be made more comfortable.Thermoregulatory drugs may also be employed to lower the trigger pointat which the patient's thermoregulatory system begins to initiatedefenses. Such drugs are described in more detail below. A methodemploying thermoregulatory drugs, heating blankets, and heat transferelements is also disclosed below.

[0134] Anatomical Placement

[0135] The internal jugular vein is the vein that directly drains thebrain. The external jugular joins the internal jugular at the base ofthe neck. The internal jugular veins join the subclavian veins to formthe brachiocephalic veins that in turn drain into the superior venacava. The superior vena cava drains into the right atrium of the heartas may be seen by referring ahead to FIG. 1. The superior vena cavasupplies blood to the heart from the upper part of the body.

[0136] A cooling element may be placed into the superior vena cava,inferior vena cava, or otherwise into a vein which feeds into thesuperior vena cava or otherwise into the heart to cool the body. Aphysician percutaneously places the catheter into the subclavian orinternal or external jugular veins to access the superior vena cava. Theblood, cooled by the heat transfer element, may be processed by theheart and provided to the body in oxygenated form to be used as aconductive medium to cool the body. The lungs have a fairly low heatcapacity, and thus the lungs do not cause appreciable rewarming of theflowing blood.

[0137] The vasculature by its very nature provides preferential bloodflow to the high blood flow organs such as the brain and the heart.Thus, these organs are preferentially cooled by such a procedure as isalso shown experimentally in FIG. 2. FIG. 2 is a graph of measuredtemperature plotted versus cooling time. This graph show the effect ofplacing a cooling element in the superior vena cavae of a sheep. Thecore body temperature as measured by an esophageal probe is shown bycurve 14. The brain temperature is shown by curve 12. The braintemperature is seen to decrease more rapidly than the core bodytemperature throughout the experiment. The inventors believe this effectto be due to the preferential supply of blood provided to the brain andheart. This effect may be even more pronounced if thermoregulatoryeffects, such as vasoconstriction, occur that tend to focus blood supplyto the core vascular system and away from the peripheral vascularsystem.

[0138] Heat Transfer

[0139] When a heat transfer element is inserted approximately coaxiallyinto an artery or vein, the primary mechanism of heat transfer betweenthe surface of the heat transfer element and the blood is forcedconvection. Convection relies upon the movement of fluid to transferheat. Forced convection results when an external force causes motionwithin the fluid. In the case of arterial or venous flow, the beatingheart causes the motion of the blood around the heat transfer element.

[0140] The magnitude of the heat transfer rate is proportional to thesurface area of the heat transfer element, the temperature differential,and the heat transfer coefficient of the heat transfer element.

[0141] The receiving artery or vein into which the heat transfer elementis placed has a limited diameter and length. Thus, the surface area ofthe heat transfer element must be limited to avoid significantobstruction of the artery or vein and to allow the heat transfer elementto easily pass through the vascular system. For placement within thesuperior vena cava via the external jugular, the cross sectionaldiameter of the heat transfer element may be limited to about 5-6 mm,and its length may be limited to approximately 10-15 cm. For placementwithin the inferior vena cava, the cross sectional diameter of the heattransfer element may be limited to about 6-7 mm, and its length may belimited to approximately 25-35 cm.

[0142] Decreasing the surface temperature of the heat transfer elementcan increase the temperature differential. However, the minimumallowable surface temperature is limited by the characteristics ofblood. Blood freezes at approximately 0° C. When the blood approachesfreezing, ice emboli may form in the blood, which may lodge downstream,causing serious ischemic injury. Furthermore, reducing the temperatureof the blood also increases its viscosity, which results in a smalldecrease in the value of the convection heat transfer coefficient. Inaddition, increased viscosity of the blood may result in an increase inthe pressure drop within the artery, thus compromising the flow of bloodto the brain. Given the above constraints, it is advantageous to limitthe minimum allowable surface temperature of the cooling element toapproximately 5° C. This results in a maximum temperature differentialbetween the blood stream and the cooling element of approximately 32° C.For other physiological reasons, there are limits on the maximumallowable surface temperature of the warming element.

[0143] The mechanisms by which the value of the convection heat transfercoefficient may be increased are complex. However, it is well known thatthe convection heat transfer coefficient increases with the level of“mixing” or “turbulent” kinetic energy in the fluid flow. Thus it isadvantageous to have blood flow with a high degree of mixing in contactwith the heat transfer element.

[0144] The blood flow has a considerably more stable flux in thesuperior vena cava than in an artery. However, the blood flow in thesuperior vena cava still has a high degree of inherent mixing orturbulence. Reynolds numbers in the superior vena cava may range, forexample, from 2,000 to 5,000. Thus, blood cooling in the superior venacava may benefit from enhancing the level of mixing with the heattransfer element but this benefit may be substantially less than thatcaused by the inherent mixing.

[0145] A thin boundary layer has been shown to form during the cardiaccycle. Boundary layers develop adjacent to the heat transfer element aswell as next to the walls of the artery or vein. Each of these boundarylayers has approximately the same thickness as the boundary layer thatwould have developed at the wall of the artery in the absence of theheat transfer element. The free stream flow region is developed in anannular ring around the heat transfer element. The heat transfer elementused in such a vessel should reduce the formation of such viscousboundary layers.

[0146] Heat Transfer Element Characteristics

[0147] The intravascular heat transfer element should be flexible inorder to be placed within the vena cavae or other veins or arteries. Theflexibility of the heat transfer element is an important characteristicbecause the same is typically inserted into a vein such as the externaljugular and accesses the superior vena cava by initially passing thougha series of one or more branches. Further, the heat transfer element isideally constructed from a highly thermally conductive material such asmetal in order to facilitate heat transfer. The use of a highlythermally conductive material increases the heat transfer rate for agiven temperature differential between the working fluid within the heattransfer element and the blood. This facilitates the use of a highertemperature coolant, or lower temperature warming fluid, within the heattransfer element, allowing safer working fluids, such as water orsaline, to be used. Highly thermally conductive materials, such asmetals, tend to be rigid. Therefore, the design of the heat transferelement should facilitate flexibility in an inherently inflexiblematerial.

[0148] It is estimated that the cooling element should absorb at leastabout 300 Watts of heat when placed in the superior vena cava to lowerthe temperature of the body to between about 30° C. and 34° C. Thesetemperatures are thought to be appropriate to obtain the benefits ofhypothermia described above. The power removed determines how quicklythe target temperature can be reached. For example, in a stroke therapyin which it is desired to lower brain temperature, the same may belowered about 4° C. per hour in a 70 kg human upon removal of 300 Watts.

[0149] One embodiment of the invention uses a modular design. Thisdesign creates helical blood flow and produces a level of mixing in theblood flow by periodically forcing abrupt changes in the direction ofthe helical blood flow. The abrupt changes in flow direction areachieved through the use of a series of two or more heat transfersegments, each included of one or more helical ridges. The use ofperiodic abrupt changes in the helical direction of the blood flow inorder to induce strong free stream turbulence may be illustrated withreference to a common clothes washing machine. The rotor of a washingmachine spins initially in one direction causing laminar flow. When therotor abruptly reverses direction, significant turbulent kinetic energyis created within the entire wash basin as the changing currents causerandom turbulent motion within the clothes-water slurry. These surfacefeatures also tend to increase the surface area of the heat transferelement, further enhancing heat transfer.

[0150] A heat transfer element with a smooth exterior surface may beable to provide the desired amount of heat transfer. However, as notedabove, it is well known that the convection heat transfer coefficientincreases with the level of turbulent kinetic energy in the fluid flow.Thus, if flow past a smooth heat transfer element will not transfersufficient heat, it is advantageous to have turbulent or otherwise mixedblood flow in contact with the heat transfer element.

[0151]FIG. 3 is a graph illustrating steady state turbulent flow. Thevertical axis is the velocity of the flow. The horizontal axisrepresents time. The average velocity of the turbulent flow is shown bya line 118. The actual instantaneous velocity of the flow is shown by acurve 116.

[0152] Under constant pressure conditions, steady flows in pipes arecharacterized as a balance between viscous stresses and the constantpressure gradient. Such flows are called Poiseuillean. FIG. 7 is avelocity profile diagram showing a typical steady state Poiseuilleanflow driven by a constant pressure gradient. The velocity of the fluidacross the pipe is shown in FIG. 7 by the parabolic curve andcorresponding velocity vectors. The velocity of the fluid in contactwith the wall of the pipe is zero. The boundary layer is the region ofthe flow in contact with the pipe surface in which viscous stresses aredominant. In steady state Poiseuillean flow, the boundary layer developsuntil it includes the whole pipe, i.e., the boundary layer thickness inFIG. 16 is one half of the diameter of the pipe.

[0153] Under conditions of Poiseuillean flow, the Reynolds number, theratio of inertial forces to viscous forces, can be used to characterizethe level of turbulent kinetic energy existing in the flow. ForPoiseuillean flows, Reynolds numbers must be greater than about 2300 tocause a transition from laminar to turbulent flow. Further, when theReynolds number is greater than about 2000, the boundary layer isreceptive to “tripping”. Tripping is a process by which a smallperturbation in the boundary layer can create turbulent conditions. Thereceptivity of a boundary layer to “tripping” is proportional to theReynolds number and is nearly zero for Reynolds numbers less than 2000.

[0154] In contrast with the steady Poiseuillean flow, the blood flow inarteries is induced by the beating heart and is therefore pulsatile. Thebelow description of this pulsatile flow, referring to FIGS. 5-19, thusdescribes the situation when a heat transfer element is inserted into anartery. FIG. 4 is a graph showing the velocity of the blood flow withinan artery as a function of time. The beating heart provides pulsatileflow with an approximate period of 0.5 to 1 second. This is known as theperiod of the cardiac cycle. The horizontal axis in FIG. 4 representstime in seconds and the vertical axis represents the average velocity ofblood in centimeters per second. Although very high velocities arereached at the peak of the pulse, the high velocity occurs for only asmall portion of the cycle. In fact, the velocity of the blood reacheszero in the carotid artery at the end of a pulse and temporarilyreverses.

[0155] Because of the relatively short duration of the cardiac pulse,the blood flow in the arteries does not develop into the classicPoiseuillean flow. FIG. 8 is a velocity profile diagram showing bloodflow velocity within an artery averaged over the cardiac pulse. Themajority of the flow within the artery has the same velocity. Theboundary layer where the flow velocity decays from the free stream valueto zero is very thin, typically ⅙ to {fraction (1/20)} of the diameterof the artery, as opposed to one half of the diameter of the artery inthe Poiseuillean flow condition.

[0156] As noted above, if the flow in the artery were steady rather thanpulsatile, the transition from laminar to turbulent flow would occurwhen the value of the Reynolds number exceeds about 2,000. However, inthe pulsatile arterial flow, the value of the Reynolds number variesduring the cardiac cycle, just as the flow velocity varies. In pulsatileflows, due to the enhanced stability associated with the acceleration ofthe free stream flow, the critical value of the Reynolds number at whichthe unstable modes of motion grow into turbulence is found to be muchhigher, perhaps as high as 9,000.

[0157] The blood flow in the arteries of interest remains laminar overmore than 80% of the cardiac cycle. Referring again to FIG. 4, the bloodflow is turbulent from approximately time t₁ until time t₂ during asmall portion of the descending systolic flow, which is less than 20% ofthe period of the cardiac cycle. If a heat transfer element is placedinside the artery, heat transfer will be facilitated during this shortinterval. However, to transfer the necessary heat to selectively coolthe brain, in arterial embodiments, turbulent kinetic energy should beproduced in the blood stream and sustained throughout the entire periodof the cardiac cycle.

[0158] A thin boundary layer has been shown to form during the cardiaccycle. This boundary layer will form over the surface of a smooth heattransfer element. FIG. 9 is a velocity profile diagram showing bloodflow velocity within an artery, averaged over the cardiac pulse, afterinsertion of a smooth heat transfer element within the artery. In FIG.9, the diameter of the heat transfer element is about one half of thediameter of the artery. Boundary layers develop adjacent to the heattransfer element as well as next to the walls of the artery. Each ofthese boundary layers has approximately the same thickness as theboundary layer which would have developed at the wall of the artery inthe absence of the heat transfer element. The free stream flow region isdeveloped in an annular ring around the heat transfer element. Bloodflow past such a smooth heat transfer element may transfer sufficientheat to accomplish the desired temperature control.

[0159] One way to increase the heat transfer rate is to create aturbulent boundary layer on the heat transfer element surface. However,turbulence in the very thin boundary layer will not produce sufficientkinetic energy to produce the necessary heat transfer rate. Therefore,to induce sufficient turbulent kinetic energy to increase the heattransfer rate sufficiently to cool the brain, a stirring mechanism,which abruptly changes the direction of velocity vectors, should beutilized. This can create high levels of turbulence intensity in thefree stream, thereby sufficiently increasing the heat transfer rate.

[0160] This turbulence intensity should ideally be sustained for asignificant portion of the cardiac cycle. Further, turbulent kineticenergy should ideally be created throughout the free stream and not justin the boundary layer. FIG. 5 is a graph illustrating the velocity ofcontinually turbulent flow under pulsatile conditions as a function oftime, which would result in optimal heat transfer in arterial bloodflow. Turbulent velocity fluctuations are seen throughout the cycle asopposed to the short interval of fluctuations seen in FIG. 4 betweentime t₁ and time t₂. These velocity fluctuations are found within thefree stream. The turbulence intensity shown in FIG. 5 is at least 0.05.In other words, the instantaneous velocity fluctuations deviate from themean velocity by at least 5%. Although, ideally, turbulence or mixing iscreated throughout the entire period of the cardiac cycle, the benefitsof turbulence are also obtained if the turbulence or mixing is sustainedfor only 75%, 50% or even as low as 30% or 20% of the cardiac cycle.

[0161] To create the desired level of turbulence intensity or mixing inthe blood free stream during the whole cardiac cycle, one embodiment ofthe invention uses a modular design. This design creates helical bloodflow and produces a high level of mixing in the free stream.

[0162] For a swirling flow in a tube in which the azimuthal velocity ofthe fluid vanishes toward the stationary outer boundary, anynon-vanishing azimuthal velocity in the interior of the flow will resultin an instability in which the inner fluid is spontaneously exchangedwith fluid near the wall, analogous to Taylor cells in the purelyazimuthal flow between a rotating inner cylinder and stationary outercylinder. This instability results from the lack of any force inopposition to the centripetal acceleration of the fluid particles movingalong helical paths, the pressure in the tube being a function only oflongitudinal position. In one embodiment, the device of the presentinvention imparts an azimuthal velocity to the interior of a developedpipe flow, with the net result being a continuous exchange of fluidbetween the core and perimeter of the flow as it moves longitudinallydown the pipe. This fluid exchange enhances the transport of heat,effectively increasing the convective heat transfer coefficient overthat which would have obtained in undisturbed pipe flow. This bulkexchange of fluid is not necessarily turbulent, although turbulence ispossible if the induced azimuthal velocity is sufficiently high.

[0163]FIG. 6 is a perspective view of such a turbulence inducing ormixing-inducing heat transfer element within an artery. In thisembodiment, turbulence or mixing is further enhanced by periodicallyforcing abrupt changes in the direction of the helical blood flow.Turbulent or mixed flow would be found at point 120, in the free streamarea. The abrupt changes in flow direction are achieved through the useof a series of two or more heat transfer segments, each comprised of oneor more helical ridges. Ideally, the segments will be close enoughtogether to prevent re-laminarization of the flow in between segments.

[0164] The use of periodic abrupt changes in the helical direction ofthe blood flow in order to induce strong free stream turbulence ormixing may be illustrated with reference to a common clothes washingmachine. The rotor of a washing machine spins initially in one directioncausing laminar flow. When the rotor abruptly reverses direction,significant turbulent kinetic energy is created within the entire washbasin as the changing currents cause random turbulent mixing motionwithin the clothes-water slurry.

[0165] A device according to an embodiment of the invention foraccomplishing such cooling or heating is shown schematically in FIG. 10,which shows a vessel wall 132 in which a blood flow 100 is passing. Acatheter 130 is disposed within the blood flow 100 to affect the bloodtemperature. Catheter 101 has an inlet lumen 126 for providing a workingfluid 107 and an outlet lumen 124 for draining the working fluid 128.The functions of the respective lumens may of course be opposite to thatstated. A reverse configuration may be particularly advantageous whenblood heating, rather than blood cooling, is the objective.

[0166] Heat transfer in this system is governed by the followingmechanisms:

[0167] (1) convective heat transfer from the blood 122 to the outletlumen 124;

[0168] (2) conduction through the wall of the outlet lumen 124;

[0169] (3) convective heat transfer from the outlet lumen 124 to theworking fluid 128;

[0170] (4) conduction through the working fluid 128;

[0171] (5) convective heat transfer from working fluid 128 in the outletlumen 124 to the inlet lumen 126; and

[0172] (6) conduction through the wall of the inlet lumen 126.

[0173] Once the materials for the lumens and the working fluid arechosen, the conductive heat transfers are solely dependent on thetemperature gradients. Convective heat transfers, by contrast, also relyon the movement of fluid to transfer heat. Forced convection resultswhen the heat transfer surface is in contact with a fluid whose motionis induced (or forced) by a pressure gradient, area variation, or othersuch force. In the case of arterial flow, the beating heart provides anoscillatory pressure gradient to force the motion of the blood incontact with the heat transfer surface. One of the aspects of the deviceuses turbulence to enhance this forced convective heat transfer.

[0174] The rate of convective heat transfer Q is proportional to theproduct of S, the area of the heat transfer element in direct contactwith the fluid, ΔT=T_(b)−T_(s), the temperature differential between thesurface temperature T_(s) of the heat transfer element and the freestream blood temperature T_(b), and {overscore (h_(c))}, the averageconvection heat transfer coefficient over the heat transfer area.{overscore (h_(c))} is sometimes called the “surface coefficient of heattransfer” or the “convection heat transfer coefficient”.

[0175] The magnitude of the heat transfer rate Q to or from the fluidflow can be increased through manipulation of the above threeparameters. Practical constraints limit the value of these parametersand how much they can be manipulated. For example, the internal diameterof the common carotid artery ranges from 6 to 8 mm. Thus, the heattransfer element residing therein may not be much larger than 4 mm indiameter to avoid occluding the vessel. The length of the heat transferelement should also be limited. For placement within the internal andcommon carotid artery, the length of the heat transfer element islimited to about 10 cm. This estimate is based on the length of thecommon carotid artery, which ranges from 8 to 12 cm. Embodimentsintended for use in the venous system would be analyzed similarly.

[0176] Consequently, the value of the surface area S is limited by thephysical constraints imposed by the size of the artery into which thedevice is placed. Surface features, such as fins, can be used toincrease the surface area of the heat transfer element, however, thesefeatures alone cannot usually provide enough surface area enhancement tomeet the required heat transfer rate. An embodiment of the devicedescribed below provides a tapered heat transfer element which employs alarge surface area but which may advantageously fit into small arteriesand veins. As the device is inflatable, the same may be inserted inrelatively small arteries and veins in a deflated state, allowing aminimally invasive entry. When the device is in position, the same maybe inflated, allowing a large surface area and thus an enhanced heattransfer rate.

[0177] One may also attempt to vary the magnitude of the heat transferrate by varying ΔT. The value of ΔT=T_(b)−T_(s) can be varied by varyingthe surface temperature T_(s) of the heat transfer element. Theallowable surface temperature of the heat transfer element is limited bythe characteristics of blood. The blood temperature is fixed at about37° C., and blood freezes at approximately 0° C. When the bloodapproaches freezing, ice emboli may form in the blood which may lodgedownstream, causing serious ischemic injury. Furthermore, reducing thetemperature of the blood also increases its viscosity which results in asmall decrease in the value of {overscore (h_(c))}. Increased viscosityof the blood may further result in an increase in the pressure dropwithin the vessel, thus compromising the flow of blood. Given the aboveconstraints, it is advantageous to limit the surface temperature of theheat transfer element to approximately 1° C.-5° C., thus resulting in amaximum temperature differential between the blood stream and the heattransfer element of approximately 32° C.-36° C.

[0178] One may also attempt to vary the magnitude of the heat transferrate by varying {overscore (h_(c))}. Fewer constraints are imposed onthe value of the convection heat transfer coefficient {overscore(h_(c))}. The mechanisms by which the value of {overscore (h_(c))} maybe increased are complex. However, one way to increase {overscore(h_(c))} for a fixed mean value of the velocity is to increase the levelof turbulent kinetic energy in the fluid flow.

[0179] The heat transfer rate Q_(no-flow) in the absence of fluid flowis proportional to ΔT, the temperature differential between the surfacetemperature T_(s) of the heat transfer element and the free stream bloodtemperature T_(b) times k, the diffusion constant, and is inverselyproportion to δ, the thickness of the boundary layer.

[0180] The magnitude of the enhancement in heat transfer by fluid flowcan be estimated by taking the ratio of the heat transfer rate withfluid flow to the heat transfer rate in the absence of fluid flowN=Q_(flow)/Q_(no-flow)={overscore (h_(c))}/(k/δ). This ratio is calledthe Nusselt number (“Nu”). For convective heat transfer between bloodand the surface of the heat transfer element, Nusselt numbers of 30-80have been found to be appropriate for selective cooling applications ofvarious organs in the human body. Nusselt numbers are generallydependent on several other numbers: the Reynolds number, the Womersleynumber, and the Prandtl number.

[0181] Stirring-type mechanisms, which abruptly change the direction ofvelocity vectors, may be utilized to induce turbulent kinetic energy andincrease the heat transfer rate. The level of turbulence so created ischaracterized by the turbulence intensity

. Turbulence intensity

is defined as the root mean square of the fluctuating velocity dividedby the mean velocity. Such mechanisms can create high levels ofturbulence intensity in the free stream, thereby increasing the heattransfer rate. This turbulence intensity should ideally be sustained fora significant portion of the cardiac cycle, and should ideally becreated throughout the free stream and not just in the boundary layer.

[0182] Turbulence does occur for a short period in the cardiac cycleanyway. In particular, the blood flow is turbulent during a smallportion of the descending systolic flow. This portion is less than 20%of the period of the cardiac cycle. If a heat transfer element is placedco-axially inside the artery, the heat transfer rate will be enhancedduring this short interval. For typical of these fluctuations, theturbulence intensity is at least 0.05. In other words, the instantaneousvelocity fluctuations deviate from the mean velocity by at least 5%.Although ideally turbulence is created throughout the entire period ofthe cardiac cycle, the benefits of turbulence are obtained if theturbulence is sustained for 75%, 50% or even as low as 30% or 20% of thecardiac cycle.

[0183] One type of turbulence-inducing heat transfer element which maybe advantageously employed to provide heating or cooling of an organ orvolume is described in U.S. Pat. No. 6,096,068 to Dobak and Lasheras fora “Selective Organ Cooling Catheter and Method of Using the Same,”incorporated by reference above. In that application, the heat transferelement is made of a high thermal conductivity material, such as metal.The metal heat transfer element provides a high degree of heat transferdue to its high thermal conductivity. In that application, bellowsprovided a high degree of articulation that compensated for theintrinsic stiffness of the metal. The device size was minimized, e.g.,less than 4 mm, to prevent blockage of the blood flowing in the artery.

[0184]FIG. 11 illustrates the dependency of the Nusselt number on theReynolds number for a fluid flowing through a long duct, i.e., airflowing though a long heated pipe at a uniform wall temperature.Although FIG. 11 illustrates this relationship for a different fluidthrough a different structure, the inventors of the present inventionbelieve a similar relationship exists for blood flow through a bloodvessel. FIG. 11 illustrates that flow is laminar when the Reynoldsnumber is below some number, in this case about 2100. In the range ofReynolds numbers between another set of numbers, in this case 2100 and10,000, a transition from laminar to turbulent flow takes place. Theflow in this regime is called transitional. The mixing caused by theheat transfer element of the present invention produces a flow that isat least transitional. At another Reynolds number, in the case above,about 10,000, the flow becomes fully turbulent.

[0185] The type of flow that occurs is important because in laminar flowthrough a duct, there is no mixing of warmer and colder fluid particlesby eddy motion. Thus, the only heat transfer that takes place is throughconduction. Since most fluids have small thermal conductivities, theheat transfer coefficients in laminar flow are relatively small. Intransitional and turbulent flow, mixing occurs through eddies that carrywarmer fluid into cooler regions and vice versa. Since the mixingmotion, even if it is only on a small scale compared to fully turbulentflow, accelerates the transfer of heat considerably, a marked increasein the heat transfer coefficient occurs above a certain Reynolds number,which in the graph of FIG. 11 is about 2100. It can be seen from FIG. 11that it is at approximately this point where the Nusselt numberincreases more dramatically. A different set of numbers may be measuredfor blood flow through an artery or vein. However, the inventors believethat a Nusselt number at least in the transitional region is importantfor enhanced heat transfer.

[0186] Device

[0187]FIG. 12 is an elevation view of one embodiment of a coolingelement 102 according to the present invention. The heat transferelement 102 includes a series of elongated, articulated segments ormodules 134,104,106. Three such segments are shown in this embodiment,but two or more such segments could be used without departing from thespirit of the invention. As seen in FIG. 12, a first elongated heattransfer segment 134 is located at the proximal end of the heat transferelement 102. A mixing-inducing exterior surface of the segment 134includes four parallel helical ridges 138 with four parallel helicalgrooves 136 therebetween. One, two, three, or more parallel helicalridges 138 could also be used without departing from the spirit of thepresent invention. In this embodiment, the helical ridges 138 and thehelical grooves 136 of the heat transfer segment 134 have a left handtwist, referred to herein as a counter-clockwise spiral or helicalrotation, as they proceed toward the distal end of the heat transfersegment 134.

[0188] The first heat transfer segment 134 is coupled to a secondelongated heat transfer segment 104 by a first bellows section 140,which provides flexibility and compressibility. The second heat transfersegment 104 includes one or more helical ridges 144 with one or morehelical grooves 142 therebetween. The ridges 144 and grooves 142 have aright hand, or clockwise, twist as they proceed toward the distal end ofthe heat transfer segment 104. The second heat transfer segment 104 iscoupled to a third elongated heat transfer segment 106 by a secondbellows section 108. The third heat transfer segment 106 includes one ormore helical ridges 148 with one or more helical grooves 146therebetween. The helical ridge 148 and the helical groove 146 have aleft hand, or counter-clockwise, twist as they proceed toward the distalend of the heat transfer segment 106. Thus, successive heat transfersegments 134, 104, 106 of the heat transfer element 102 alternatebetween having clockwise and counterclockwise helical twists. The actualleft or right hand twist of any particular segment is immaterial, aslong as adjacent segments have opposite helical twist.

[0189] In addition, the rounded contours of the ridges 138, 144, 148allow the heat transfer element 102 to maintain a relatively atraumaticprofile, thereby minimizing the possibility of damage to the bloodvessel wall. A heat transfer element according to the present inventionmay include two, three, or more heat transfer segments.

[0190] The bellows sections 140, 108 are formed from seamless andnonporous materials, such as metal, and therefore are impermeable togas, which can be particularly important, depending on the type ofworking fluid that is cycled through the heat transfer element 102. Thestructure of the bellows sections 140, 108 allows them to bend, extendand compress, which increases the flexibility of the heat transferelement 102 so that it is more readily able to navigate through bloodvessels. The bellows sections 140, 108 also provide for axialcompression of the heat transfer element 102, which can limit the traumawhen the distal end of the heat transfer element 102 abuts a bloodvessel wall. The bellows sections 140, 108 are also able to toleratecryogenic temperatures without a loss of performance. In alternativeembodiments, the bellows may be replaced by flexible polymer tubes,which are bonded between adjacent heat transfer segments.

[0191] The exterior surfaces of the heat transfer element 102 can bemade from metal, and may include very high thermal conductivitymaterials such as nickel, thereby facilitating heat transfer.Alternatively, other metals such as stainless steel, titanium, aluminum,silver, copper and the like, can be used, with or without an appropriatecoating or treatment to enhance biocompatibility or inhibit clotformation. Suitable biocompatible coatings include, e.g., gold, platinumor polymer paralyene. The heat transfer element 102 may be manufacturedby plating a thin layer of metal on a mandrel that has the appropriatepattern. In this way, the heat transfer element 102 may be manufacturedinexpensively in large quantities, which is an important feature in adisposable medical device.

[0192] Because the heat transfer element 102 may dwell within the bloodvessel for extended periods of time, such as 24-48 hours or even longer,it may be desirable to treat the surfaces of the heat transfer element102 to avoid clot formation. In particular, one may wish to treat thebellows sections 140, 108 because stagnation of the blood flow may occurin the convolutions, thus allowing clots to form and cling to thesurface to form a thrombus. One means by which to prevent thrombusformation is to bind an antithrombogenic agent to the surface of theheat transfer element 102. For example, heparin is known to inhibit clotformation and is also known to be useful as a biocoating. Alternatively,the surfaces of the heat transfer element 102 may be bombarded with ionssuch as nitrogen. Bombardment with nitrogen can harden and smooth thesurface and thus prevent adherence of clotting factors. Another coatingthat provides beneficial properties may be a lubricious coating.Lubricious coatings, on both the heat transfer element and itsassociated catheter, allow for easier placement in the, e.g., vena cava.

[0193]FIG. 13 is a longitudinal sectional view of the heat transferelement 102 of an embodiment of the invention, taken along line 2-2 inFIG. 12. Some interior contours are omitted for purposes of clarity. Aninner tube 150 creates an inner lumen 158 and an outer lumen 156 withinthe heat transfer element 102. Once the heat transfer element 102 is inplace in the blood vessel, a working fluid such as saline or otheraqueous solution may be circulated through the heat transfer element102. Fluid flows up a supply catheter into the inner lumen 158. At thedistal end of the heat transfer element 102, the working fluid exits theinner lumen 158 and enters the outer lumen 156. As the working fluidflows through the outer lumen 156, heat is transferred from the workingfluid to the exterior surface 152 of the heat transfer element 102.Because the heat transfer element 102 is constructed from a highconductivity material, the temperature of its exterior surface 152 mayreach very close to the temperature of the working fluid. The tube 150may be formed as an insulating divider to thermally separate the innerlumen 158 from the outer lumen 156. For example, insulation may beachieved by creating longitudinal air channels in the wall of theinsulating tube 150. Alternatively, the insulating tube 150 may beconstructed of a non-thermally conductive material likepolytetrafluoroethylene or another polymer.

[0194] It is important to note that the same mechanisms that govern theheat transfer rate between the exterior surface 152 of the heat transferelement 102 and the blood also govern the heat transfer rate between theworking fluid and the interior surface 154 of the heat transfer element102. The heat transfer characteristics of the interior surface 154 areparticularly important when using water, saline or other fluid thatremains a liquid as the working fluid. Other coolants such as Freonundergo nucleate boiling and create mixing through a differentmechanism. Saline is a safe working fluid, because it is non-toxic, andleakage of saline does not result in a gas embolism, which could occurwith the use of boiling refrigerants. Since mixing in the working fluidis enhanced by the shape of the interior surface 154 of the heattransfer element 102, the working fluid can be delivered to the coolingelement 102 at a warmer temperature and still achieve the necessarycooling rate. Similarly, since mixing in the working fluid is enhancedby the shape of the interior surface of the heat transfer element, theworking fluid can be delivered to the warming element 102 at a coolertemperature and still achieve the necessary warming rate.

[0195] This has a number of beneficial implications in the need forinsulation along the catheter shaft length. Due to the decreased needfor insulation, the catheter shaft diameter can be made smaller. Theenhanced heat transfer characteristics of the interior surface of theheat transfer element 102 also allow the working fluid to be deliveredto the heat transfer element 102 at lower flow rates and lowerpressures. High pressures may make the heat transfer element stiff andcause it to push against the wall of the blood vessel, thereby shieldingpart of the exterior surface 152 of the heat transfer element 102 fromthe blood. Because of the increased heat transfer characteristicsachieved by the alternating helical ridges 138, 144, 148, the pressureof the working fluid may be as low as 5 atmospheres, 3 atmospheres, 2atmospheres or even less than 1 atmosphere.

[0196]FIG. 14 is a transverse sectional view of the heat transferelement 102 of the invention, taken at a location denoted by the line3-3 in FIG. 12. FIG. 14 illustrates a five-lobed embodiment, whereasFIG. 12 illustrates a four-lobed embodiment. As mentioned earlier, anynumber of lobes might be used. In FIG. 14, the construction of the heattransfer element 102 is clearly shown. The inner lumen 158 is defined bythe insulating tube 150. The outer lumen 156 is defined by the exteriorsurface of the insulating tube 150 and the interior surface 154 of theheat transfer element 102. In addition, the helical ridges 144 andhelical grooves 142 may be seen in FIG. 14. Although FIG. 14 shows fourridges and four grooves, the number of ridges and grooves may vary.Thus, heat transfer elements with 1, 2, 3, 4, 5, 6, 7, 8 or more ridgesare specifically contemplated.

[0197]FIG. 15 is a perspective view of a heat transfer element 102 inuse within a blood vessel, showing only one helical lobe per segment forpurposes of clarity. Beginning from the proximal end of the heattransfer element (not shown in FIG. 15), as the blood moves forward, thefirst helical heat transfer segment 134 induces a counter-clockwiserotational inertia to the blood. As the blood reaches the second segment104, the rotational direction of the inertia is reversed, causing mixingwithin the blood. Further, as the blood reaches the third segment 106,the rotational direction of the inertia is again reversed. The suddenchanges in flow direction actively reorient and randomize the velocityvectors, thus ensuring mixing throughout the bloodstream. During suchmixing, the velocity vectors of the blood become more random and, insome cases, become perpendicular to the axis of the vessel. Thus, alarge portion of the volume of warm blood in the vessel is activelybrought in contact with the heat transfer element 102 where it can becooled by direct contact rather than being cooled largely by conductionthrough adjacent laminar layers of blood.

[0198] Referring back to FIG. 12, the heat transfer element 102 has beendesigned to address all of the design criteria discussed above. First,the heat transfer element 102 is flexible and is made of a highlyconductive material. The flexibility is provided by a segmentaldistribution of bellows sections 140, 108 that provide an articulatingmechanism. Bellows have a known convoluted design that provideflexibility. Second, the exterior surface area 152 has been increasedthrough the use of helical ridges 138, 144, 148 and helical grooves 136,142, 146. The ridges also allow the heat transfer element 102 tomaintain a relatively atraumatic profile, thereby minimizing thepossibility of damage to the vessel wall. Third, the heat transferelement 102 has been designed to promote mixing both internally andexternally. The modular or segmental design allows the direction of thegrooves to be reversed between segments. The alternating helicalrotations create an alternating flow that results in mixing the blood ina manner analogous to the mixing action created by the rotor of awashing machine that switches directions back and forth. This action isintended to promote mixing to enhance the heat transfer rate. Thealternating helical design also causes beneficial mixing, or turbulentkinetic energy, of the working fluid flowing internally.

[0199]FIG. 16 is a perspective view of a third embodiment of a heattransfer element 160 according to the present invention. The heattransfer element 160 is comprised of a series of elongated, articulatedsegments or modules 162. A first elongated heat transfer segment 162 islocated at the proximal end of the heat transfer element 160. Thesegment 162 may be a smooth right circular cylinder, as addressed inFIG. 9, or it can incorporate a turbulence-inducing or mixing-inducingexterior surface. The turbulence-inducing or mixing-inducing exteriorsurface shown on the segment 162 in FIG. 16 comprises a plurality ofparallel longitudinal ridges 164 with parallel longitudinal grooves 168therebetween. One, two, three, or more parallel longitudinal ridges 164could be used without departing from the spirit of the presentinvention. In the embodiment where they are used, the longitudinalridges 164 and the longitudinal grooves 168 of the heat transfer segment162 are aligned parallel with the axis of the first heat transfersegment 162.

[0200] The first heat transfer segment 162 is coupled to a secondelongated heat transfer segment 162 by a first flexible section such asa bellows section 166, which provides flexibility and compressibility.Alternatively, the flexible section may be a simple flexible tube, verysimilar to a smooth heat transfer segment as addressed in FIG. 9, butflexible. The second heat transfer segment 162 also comprises aplurality of parallel longitudinal ridges 164 with parallel longitudinalgrooves 168 therebetween. The longitudinal ridges 164 and thelongitudinal grooves 168 of the second heat transfer segment 162 arealigned parallel with the axis of the second heat transfer segment 162.The second heat transfer segment 162 is coupled to a third elongatedheat transfer segment 162 by a second flexible section such as a bellowssection 166 or a flexible tube. The third heat transfer segment 162 alsocomprises a plurality of parallel longitudinal ridges 164 with parallellongitudinal grooves 168 therebetween. The longitudinal ridges 164 andthe longitudinal grooves 168 of the third heat transfer segment 162 arealigned parallel with the axis of the third heat transfer segment 162.Further, in this embodiment, adjacent heat transfer segments 162 of theheat transfer element 160 have their longitudinal ridges 164 alignedwith each other, and their longitudinal grooves 168 aligned with eachother.

[0201] In addition, the rounded contours of the ridges 164 also allowthe heat transfer element 160 to maintain a relatively atraumaticprofile, thereby minimizing the possibility of damage to the bloodvessel wall. A heat transfer element 160 according to the presentinvention may be comprised of two, three, or more heat transfer segments162.

[0202] The bellows sections 166 are formed from seamless and nonporousmaterials, such as metal, and therefore are impermeable to gas, whichcan be particularly important, depending on the type of working fluidwhich is cycled through the heat transfer element 160. The structure ofthe bellows sections 166 allows them to bend, extend and compress, whichincreases the flexibility of the heat transfer element 160 so that it ismore readily able to navigate through blood vessels. The bellowssections 166 also provide for axial compression of the heat transferelement 160, which can limit the trauma when the distal end of the heattransfer element 160 abuts a blood vessel wall. The bellows sections 166are also able to tolerate cryogenic temperatures without a loss ofperformance.

[0203]FIG. 17 is a perspective view of a fourth embodiment of a heattransfer element 170 according to the present invention. The heattransfer element 170 is comprised of a series of elongated, articulatedsegments or modules 172. A first elongated heat transfer segment 172 islocated at the proximal end of the heat transfer element 170. Aturbulence-inducing or mixing-inducing exterior surface of the segment172 comprises a plurality of parallel longitudinal ridges 174 withparallel longitudinal grooves 176 therebetween. One, two, three, or moreparallel longitudinal ridges 174 could be used without departing fromthe spirit of the present invention. In this embodiment, thelongitudinal ridges 174 and the longitudinal grooves 176 of the heattransfer segment 172 are aligned parallel with the axis of the firstheat transfer segment 172.

[0204] The first heat transfer segment 172 is coupled to a secondelongated heat transfer segment 172 by a first flexible section such asa bellows section 178, which provides flexibility and compressibility.Alternatively, the flexible section may be a simple flexible tube, verysimilar to a smooth heat transfer segment as shown in FIG. 9, butflexible. The second heat transfer segment 172 also comprises aplurality of parallel longitudinal ridges 174 with parallel longitudinalgrooves 176 therebetween. The longitudinal ridges 174 and thelongitudinal grooves 176 of the second heat transfer segment 172 arealigned parallel with the axis of the second heat transfer segment 172.The second heat transfer segment 172 is coupled to a third elongatedheat transfer segment 172 by a second flexible section such as a bellowssection 178 or a flexible tube. The third heat transfer segment 172 alsocomprises a plurality of parallel longitudinal ridges 174 with parallellongitudinal grooves 176 therebetween. The longitudinal ridges 174 andthe longitudinal grooves 176 of the third heat transfer segment 172 arealigned parallel with the axis of the third heat transfer segment 172.Further, in this embodiment, adjacent heat transfer segments 172 of theheat transfer element 170 have their longitudinal ridges 174 angularlyoffset from each other, and their longitudinal grooves 176 angularlyoffset from each other. Offsetting of the longitudinal ridges 174 andthe longitudinal grooves 176 from each other on adjacent segments 172promotes turbulence or mixing in blood flowing past the exterior of theheat transfer element 170.

[0205]FIG. 18 is a transverse section view of a heat transfer segment180, illustrative of segments 162, 172 of heat transfer elements 160,170 shown in FIG. 16 and FIG. 17. The coaxial construction of the heattransfer segment 180 is clearly shown. The inner coaxial lumen 182 isdefined by the insulating coaxial tube 184. The outer lumen 190 isdefined by the exterior surface of the insulating coaxial tube 184 andthe interior surface 192 of the heat transfer segment 180. In addition,parallel longitudinal ridges 186 and parallel longitudinal grooves 188may be seen in FIG. 18. The longitudinal ridges 186 and the longitudinalgrooves 188 may have a relatively rectangular cross-section, as shown inFIG. 18, or they may be more triangular in cross-section, as shown inFIGS. 16 and 17. The longitudinal ridges 186 and the longitudinalgrooves 188 may be formed only on the exterior surface of the segment180, with a cylindrical interior surface 192. Alternatively,corresponding longitudinal ridges and grooves may be formed on theinterior surface 192 as shown, to promote turbulence or mixing in theworking fluid. Although FIG. 18 shows six ridges and six grooves, thenumber of ridges and grooves may vary. Where a smooth exterior surfaceis desired, the outer tube of the heat transfer segment 180 could havesmooth outer and inner surfaces, like the inner tube 184. Alternatively,the outer tube of the heat transfer segment 180 could have a smoothouter surface and a ridged inner surface like the interior surface 192shown in FIG. 18.

[0206]FIG. 19 is a cut-away perspective view of an alternativeembodiment of a heat transfer element 194. An external surface 196 ofthe heat transfer element 194 is covered with a series of axiallystaggered protrusions 198. The staggered nature of the outer protrusions198 is readily seen with reference to FIG. 20 which is a transversecross-sectional view taken at a location denoted by the line 6-6 in FIG.19. As the blood flows along the external surface 196, it collides withone of the staggered protrusions 198 and a turbulent wake flow iscreated behind the protrusion. As the blood divides and swirls alongsideof the first staggered protrusion 198, its turbulent wake encountersanother staggered protrusion 198 within its path preventing there-lamination of the flow and creating yet more mixing. In this way, thevelocity vectors are randomized and mixing is created not only in theboundary layer but also throughout a large portion of the free stream.As is the case with the preferred embodiment, this geometry also inducesa mixing effect on the internal working fluid flow.

[0207] A working fluid is circulated up through an inner lumen 200defined by an insulating tube 202 to a distal tip of the heat transferelement 194. The working fluid then traverses an outer lumen 204 inorder to transfer heat to the exterior surface 196 of the heat transferelement 194. The inside surface of the heat transfer element 194 issimilar to the exterior surface 196 in order to induce turbulent flow ofthe working fluid. The inner protrusions can be aligned with the outerprotrusions 198 as shown in FIG. 20 or they can be offset from the outerprotrusions 198 as shown in FIG. 19.

[0208] With reference to FIGS. 21 and 22, a catheter 206 constructed inaccordance with an alternative embodiment of the invention will now bedescribed. The catheter 206 includes an elongated catheter body 208 witha heat transfer element 210 located at a distal portion 212 of thecatheter body 208. The catheter 206 includes a multiple lumenarrangement 214 to deliver fluid to and from an interior 216 of the heattransfer element 210 and allow the catheter 206 to be placed into ablood vessel over a guidewire. The heat transfer element 210 includesturbulence-inducing invaginations 218 located on an exterior surface252. Similar invaginations may be located on an interior surface 220 ofthe heat transfer element 210, but are not shown for clarity. Further,it should be noted that the heat transfer element 210 is shown with onlyfour invaginations 218. Other embodiments may employ multiple elementsconnected by flexible joints or bellows as disclosed above. A singleheat transfer element is shown in FIG. 21 merely for clarity. In analternative embodiment of the invention, any of the other heat-transferelements described herein may replace heat transfer element 212.Alternatively, the multi-lumen arrangement may be used to deliver fluidto and from the interior of an operative element(s) other than aheat-transfer-element such as, but without limitation, a catheterballoon, e.g., a dilatation balloon.

[0209] The catheter 206 includes an integrated elongated multiple lumenmember such as a bi-lumen member 222 having a first lumen member 226 anda second lumen member 228. The bi-lumen member 222 has a substantiallyfigure-eight cross-sectional shape (FIG. 22) and an outer surface 224with the same general shape. The first lumen member 226 includes aninterior surface 230 defining a first lumen or guide wire lumen 232having a substantially circular cross-sectional shape. The interiorsurface 230 may be coated with a lubricious material to facilitate thesliding of the catheter 206 over a guidewire. The first lumen member 226further includes a first exterior surface 242 and a second exteriorsurface 244. The first lumen 232 is adapted to receive a guide wire forplacing the catheter 206 into a blood vessel over the guidewire in awell-known manner.

[0210] In FIGS. 21 and 22, the guide wire lumen 232 is not coaxial withthe catheter body 208. In an alternative embodiment of the invention,the guide wire lumen 232 may be coaxial with the catheter body 208.

[0211] The second lumen member 228 includes a first interior surface 246and a second interior surface 248, which is the same as the secondexterior surface 244 of the first lumen member 226, that together definea second lumen or supply lumen 250 having a substantially luniformcross-sectional shape. The second lumen member 228 further includes anexterior surface 252. The second lumen 250 has a cross-sectional areaA₂. The second lumen 250 is adapted to supply working fluid to theinterior of the heat transfer element 210 to provide temperature controlof a flow or volume of blood in the manner described above.

[0212] The second lumen member 228 terminates short of a distal end 236of the catheter 206, leaving sufficient space for the working fluid toexit the supply lumen 250 so it can contact the interior surface 220 ofthe heat transfer element 210 for heat transfer purposes.

[0213] Although the second lumen member 228 is shown as a single supplylumen terminating adjacent the distal end 236 of catheter 206 to deliverworking fluid at the distal end of the catheter 206, with reference toFIG. 23, in an alternative embodiment of the invention, a single supplylumen member 254 may include one or more outlet openings 256 adjacentthe distal end 236 of the catheter 206 and one or more outlet openings258 adjacent a mid-point along the interior length of the heat transferelement 210. This arrangement improves the heat transfer characteristicsof the heat-transfer element 210 because fresh working fluid at the sametemperature is delivered separately to each segment 104, 106 of theinterior of the heat-transfer element 210 instead of in series.

[0214] Although two heat transfer segments 104, 106 are shown, it willbe readily apparent that a number of heat transfer segments other thantwo, e.g., one, three, four, etc., may be used.

[0215] It will be readily apparent to those skilled in the art that inanother embodiment of the invention, in addition to the one or moreopenings 256 in the distal portion of the heat transfer element 210, oneor more openings at one or more locations may be located anywhere alongthe interior length of the heat transfer element 210 proximal to thedistal portion.

[0216] With reference to FIG. 24, in an alternative embodiment of theinvention, first and second supply lumen members 260, 262 definerespective first and second supply lumens 264, 266 for supplying workingfluid to the interior of the heat transfer element 210. The first supplylumen 260 terminates just short of the distal end 236 of the catheter206 to deliver working fluid at the distal portion of the heat transferelement 210. The second supply lumen 262 terminates short of the distalportion of the catheter 206, for example, at approximately a mid-lengthpoint along the interior of the heat transfer element 210 for deliveringworking fluid to the second heat transfer segment 104. In an alternativeembodiment of the invention, the second lumen member 262 may terminateanywhere along the interior length of the heat transfer element 210proximal to the distal portion of the heat transfer element 210.Further, a number of supply lumens 262 greater than two may terminatealong the interior length of the heat transfer element 210 fordelivering a working fluid at a variety of points along the interiorlength of the heat transfer element 210.

[0217] With reference back to FIGS. 21 and 22, the bi-lumen member 222is preferably extruded from a material such as polyurethane or Pebax. Inan embodiment of the invention, the bi-lumen member is extrudedsimultaneously with the catheter body 208. In an alternative embodimentof the invention, the first lumen member 226 and second lumen member 228are formed separately and welded or fixed together.

[0218] A third lumen or return lumen 238 provides a convenient returnpath for working fluid. The third lumen 238 is substantially defined bythe interior surface 220 of the heat transfer element 210, an interiorsurface 240 of the catheter body 208, and the exterior surface 224 ofthe bi-lumen member 222. The inventors have determined that the workingfluid pressure drop through the lumens is minimized when the third lumen238 has a hydraulic diameter D₃ that is equal to 0.75 of the hydraulicdiameter D₂ of the second lumen 250. However, the pressure drop thatoccurs when the ratio of the hydraulic diameter D₃to the hydraulicdiameter D₂ is substantially equal to 0.75, i.e., 0.75±0.10, works well.For flow through a cylinder, the hydraulic diameter D of a lumen isequal to four times the cross-sectional area of the lumen divided by thewetted perimeter. The wetted perimeter is the total perimeter of theregion defined by the intersection of the fluid path through the lumenand a plane perpendicular to the longitudinal axis of the lumen. Thewetted perimeter for the return lumen 238 would include an inner wettedperimeter (due to the outer surface 224 of the bi-lumen member 222) andan outer wetted perimeter (due to the interior surface 240 of thecatheter body 208). The wetted perimeter for the supply lumen 250 wouldinclude only an outer wetted perimeter (due to the first and secondinterior surfaces 246, 248 of the bi-lumen member 222). Thus, the wettedperimeter for a lumen depends on the number of boundary surfaces thatdefine the lumen.

[0219] The third lumen 238 is adapted to return working fluid deliveredto the interior of the heat transfer element 210 back to an externalreservoir or the fluid supply for recirculation in a well-known manner.

[0220] In an alternative embodiment, the third lumen 238 is the supplylumen and the second lumen 250 is the return lumen. Accordingly, it willbe readily understood by the reader that adjectives such as “first,”“second,” etc. are used to facilitate the reader's understanding of theinvention and are not intended to limit the scope of the invention,especially as defined in the claims.

[0221] In a further embodiment of the invention, the member 222 mayinclude a number of lumens other than two such as, for example, 1, 3, 4,5, etc. Additional lumens may be used as additional supply and/or returnlumens, for other instruments, e.g., imaging devices, or for otherpurposes, e.g., inflating a catheter balloon or delivering a drug.

[0222] Heating or cooling efficiency of the heat transfer element 210 isoptimized by maximizing the flow rate of working fluid through thelumens 250, 238 and minimizing the transfer of heat between the workingfluid and the supply lumen member. Working fluid flow rate is maximizedand pressure drop minimized in the present invention by having the ratioof the hydraulic diameter D₃ of the return lumen 238 to the hydraulicdiameter D₂ of the supply lumen 250 equal to 0.75. However, a ratiosubstantially equal to 0.75, i.e., 0.75±10-20%, is acceptable. Heattransfer losses are minimized in the supply lumen 250 by minimizing thesurface area contact made between the bi-lumen member 222 and theworking fluid as it travels through the supply lumen member. The surfacearea of the supply lumen member that the supplied working fluid contactsis much less than that in co-axial or concentric lumens used in the pastbecause the supplied working fluid only contacts the interior of onelumen member compared to contacting the exterior of one lumen member andthe interior of another lumen member. Thus, heat transfer losses areminimized in the embodiments of the supply lumen in the multiple lumenmember 222 of the present invention.

[0223] It will be readily apparent to those skilled in the art that thesupply lumen 250 and the return lumen 238 may have cross-sectionalshapes other than those shown and described herein and still maintainthe desired hydraulic diameter ratio of substantially 0.75. Withreference to FIGS. 25 and 26, an example of a catheter 206 including asupply lumen and a return lumen constructed in accordance with analternative preferred embodiment of the invention, where the hydraulicdiameter ratio of the return lumen to the supply lumen is substantiallyequal to 0.75 is illustrated. It should be noted, the same elements asthose described above with respect to FIGS. 21 and 22 are identifiedwith the same reference numerals and similar elements are identifiedwith the same reference numerals, but with a (′) suffix.

[0224] The catheter 206 illustrated in FIGS. 25 and 26 includes amultiple lumen arrangement 214′ for delivering working fluid to and froman interior 216 of the heat transfer element 210 and allowing thecatheter to be placed into a blood vessel over a guide wire. Themultiple lumen arrangement 214′ includes a bi-lumen member 222′ with aslightly different construction from the bi-lumen member 222 discussedabove with respect to FIGS. 21 and 22. Instead of an outer surface 224that is generally figure-eight shaped, the bi-lumen member 222′ has anouter surface 224′ that is circular. Consequently, the third lumen 238′has an annular cross-sectional shape.

[0225] As discussed above, maintaining the hydraulic diameter ratio ofthe return lumen 250′ to the supply lumen 238′ substantially equal to0.75 maximizes the working fluid flow rate through the multiple lumenarrangement 214′.

[0226] In addition, the annular return lumen 238′ enhances theconvective heat transfer coefficient within the heat transfer element210, especially adjacent an intermediate segment or bellows segment 268.Working fluid flowing through the annular return lumen 238′, between theouter surface 224′ of the bi-lumen member 222′ and the inner surface 220of the heat transfer element, encounters a restriction 270 caused by theimpingement of the bellows section 268 into the flow path. Although theimpingement of the bellows section 268 is shown as causing therestriction 270 in the flow path of the return lumen 238′, in analternative embodiment of the invention, the bi-lumen member 222′ maycreate the restriction 270 by being thicker in this longitudinal regionof the bi-lumen member 222′. The distance between the bi-lumen member222′ and the bellows section 268 is such that the characteristic flowresulting from a flow of working fluid is at least of a transitionalnature.

[0227] For a specific working fluid flux or flow rate (cc/sec), the meanfluid velocity through the bellows section restriction 270 will begreater than the mean fluid velocity obtained through the annular returnlumen 238′ in the heat transfer segment 104, 106 of the heat transferelement 210. Sufficiently high velocity through the bellows sectionrestriction 270 will result in wall jets 272 directed into the interiorportion 220 of the heat transfer segment 104. The wall jets 272 enhancethe heat transfer coefficient within the helical heat transfer segment104 because they enhance the mixing of the working fluid along theinterior of the helical heat transfer segment 104. Increasing thevelocity of the jets 272 by increasing the working fluid flow rate ordecreasing the size of the restriction 270 will result in a transitioncloser to the jet exit and greater mean turbulence intensity throughoutthe helical heat transfer segment 104. Thus, the outer surface 224′ ofthe bi-lumen member 222′, adjacent the bellows 268, and the innersurface of the bellows 268 form means for further enhancing the transferof heat between the heat transfer element 210 and the working fluid, inaddition to that caused by the interior portion 220 of the helical heattransfer segment 104.

[0228] In an alternative embodiment of the invention, as describedabove, the heat transfer element may include a number of heat transfersegments other than two, i.e., 1, 3, 4, etc., with a correspondingnumber of intermediate segments, i.e., the number of heat transfersegments minus one.

[0229] The embodiment of the multiple lumen arrangement 222 discussedwith respect to FIGS. 21 and 22 would not enhance the convective heattransfer coefficient as much as the embodiment of the multiple lumenarrangement 222′ discussed with respect to FIGS. 25 and 26 becauseworking fluid would preferentially flow through the larger areas of thereturn lumen 238, adjacent the junction of the first lumen member 226and second lumen member 228. Thus, high-speed working fluid would havemore contact with the outer surface 224 of the bi-lumen member 222 andless contact with the interior portion of 220 heat transfer element 210.In contrast, the annular return lumen 238′ of the multiple lumenarrangement 222′ causes working fluid flow to be axisymmetric so thatsignificant working fluid flow contacts all areas of the helical segmentequally.

[0230] On the other hand, the heat transfer element according to anembodiment of the present invention may also be made of a flexiblematerial, such as latex rubber. The latex rubber provides a high degreeof flexibility which was previously achieved by articulation. The latexrubber further allows the heat transfer element to be made collapsibleso that when deflated the same may be easily inserted into an artery.Insertion and location may be conveniently made by way of a guidecatheter or guide wire. Following insertion and location in the desiredartery, the heat transfer element may be inflated for use by a workingfluid such as saline, water, perfluorocarbons, or other suitable fluids.

[0231] A heat transfer element made of a flexible material generally hassignificantly less thermal conductivity than a heat transfer elementmade of metal. The device compensates for this by enhancing the surfacearea available for heat transfer. This may be accomplished in two ways:by increasing the cross-sectional size and by increasing the length.Regarding the former, the device may be structured to be large wheninflated, because when deflated the same may still be inserted into anartery. In fact, the device may be as large as the arterial wall, solong as a path for blood flow is allowed, because the flexibility of thedevice tends to prevent damage to the arterial wall even upon contact.Such paths are described below. Regarding the latter, the device may beconfigured to be long. One way to configure a long device is to taperthe same so that the device may fit into distal arteries having reducedradii in a manner described below. The device further compensates forthe reduced thermal conductivity by reducing the thickness of the heattransfer element wall.

[0232] Embodiments of the device use a heat transfer element design thatproduces a high level of turbulence in the free stream of the blood andin the working fluid. One embodiment of the invention forces a helicalmotion on the working fluid and imposes a helical barrier in the blood,causing turbulence. In an alternative embodiment, the helical barrier istapered. In a second alternative embodiment, a tapered inflatable heattransfer element has surface features to cause turbulence. As oneexample, the surface features may have a spiral shape. In anotherexample, the surface features may be staggered protrusions. In all ofthese embodiments, the design forces a high level of turbulence in thefree stream of the blood by causing the blood to navigate a tortuouspath while passing through the artery. This tortuous path causes theblood to undergo violent accelerations resulting in turbulence.

[0233] In a third alternative embodiment of the invention, a taper of aninflatable heat transfer element provides enough additional surface areaper se to cause sufficient heat transfer. In all of the embodiments, theinflation is performed by the working fluid, such as water or saline.

[0234] Referring to FIG. 27, a side view is shown of a first embodimentof a heat transfer element 272 according to an embodiment of theinvention. The heat transfer element 272 is formed by an inlet lumen 276and an outlet lumen 274. In this embodiment, the outlet lumen 274 isformed in a helix shape surrounding the inlet lumen 276 that is formedin a pipe shape. The names of the lumens are of course not limiting. Itwill be clear to one skilled in the art that the inlet lumen 276 mayserve as an outlet and the outlet lumen 274 may serve as an inlet. Itwill also be clear that the heat transfer element is capable of bothheating (by delivering heat to) and cooling (by removing heat from) adesired area.

[0235] The heat transfer element 272 is rigid but flexible so as to beinsertable in an appropriate vessel by use of a guide catheter.Alternatively, the heat transfer element may employ a device forthreading a guide wire therethrough to assist placement within anartery. The heat transfer element 272 has an inflated length of L, ahelical diameter of D_(c), a tubal diameter of d, and a helical angle ofα. For example, D_(c) may be about 3.3 mm and d may be about 0.9 mm to 1mm. Of course, the tubal diameter d need not be constant. For example,the diameter of the inlet lumen 276 may differ from that of the outletlumen 272.

[0236] The shape of the outlet lumen 274 in FIG. 27 is helical. Thishelical shape presents a cylindrical obstacle, in cross-section, to theflow of blood. Such obstacles tend to create turbulence in the freestream of blood. In particular, the form of turbulence is the creationof von Karman vortices in the wake of the flow of blood, downstream ofthe cylindrical obstacles.

[0237] Typical inflatable materials are not highly thermally conductive.They are much less conductive than the metallic heat transfer elementdisclosed in the patent application incorporated by reference above. Thedifference in conductivity is compensated for in at least two ways inthe present device. The material is made thinner and the heat transferelement is afforded a larger surface area. Regarding the former, thethickness may be less than about ½ mil for adequate cooling.

[0238] Thin inflatable materials, particularly those with large surfaceareas, may require a structure, such as a wire, within their interiorsto maintain their approximate uninflated positions so that uponinflation, the proper form is achieved. Thus, a wire structure 282 isshown in FIG. 27 which may be advantageously disposed within theinflatable material to perform such a function.

[0239] Another consideration is the angle α of the helix. Angle α shouldbe determined to optimize the helical motion of the blood around thelumens 274 and 276, enhancing heat transfer. Of course, angle α shouldalso be determined to optimize the helical motion of the working fluidwithin the lumens 274 and 276. The helical motion of the working fluidwithin the lumens 274 and 276 increases the turbulence in the workingfluid by creating secondary motions. In particular, helical motion of afluid in a pipe induces two counter-rotating secondary flows.

[0240] An enhancement of {overscore (h_(c))} would be obtained in thissystem, and this enhancement may be described by a Nusselt number Nu ofup to about 10 or even more.

[0241] The above discussion describes one embodiment of a heat transferelement. An alternative embodiment of the device, shown in a side viewin FIG. 28, illustrates a heat transfer element 286 with a surface areaenhancement. Increasing the surface area of the inflatable materialenhances heat transfer. The heat transfer element 272 includes a seriesof coils or helices of different coil diameters and tubal diameters. Itis not strictly necessary that the tubal diameters differ, but it islikely that commercially realizable systems will have differing tubaldiameters. The heat transfer element 272 may taper either continuouslyor segmentally.

[0242] This alternative embodiment enhances surface area in two ways.First, the use of smaller diameter lumens enhances the overallsurface-to-volume ratio. Second, the use of progressively smaller (i.e.,tapered) lumens allows a distal end 312 to be inserted further into anartery than would be possible with the embodiment of FIG. 27.

[0243] In the embodiment of FIG. 28, a first coil segment 288 is shownhaving length L₁ and diameter D_(c1). The first coil segment 288 isformed of an inlet lumen 296 having diameter d₁ and an outlet lumen 298having diameter d₁′. In the first coil segment, as well as the others,the outlet lumen need not immediately drain the inlet lumen. In FIG. 28,the inlet lumen for each segment feeds the inlet lumen of the succeedingsegment except for an inlet lumen adjacent a distal end 312 of the heattransfer element 286 which directly feeds its corresponding outletlumen.

[0244] A separate embodiment may also be constructed in which the inletlumens each provide working fluid to their corresponding outlet lumens.In this embodiment, either a separate lumen needs to be provided todrain each outlet lumen or each outlet lumen drains into the adjacentoutlet lumen. This embodiment has the advantage that an oppositehelicity may be accorded each successive segment. The oppositehelicities in turn enhance the turbulence of the working fluid flowingpast them.

[0245] A second coil segment 290 is shown having length L₂ and diameterD_(c2). The second coil segment 290 is formed of an inlet lumen 300having diameter d₂ and an outlet lumen 302 having diameter d₂′. A thirdcoil segment 292 is shown having length L₃ and diameter DC₃. The thirdcoil segment 292 is formed of an inlet lumen 304 having diameter d₃ andan outlet lumen 306 having diameter d₃′. Likewise, a fourth coil segment294 is shown having length L₄ and diameter D_(c4). The fourth coilsegment 294 is formed of an inlet lumen 308 having diameter d₄ and anoutlet lumen 310 having diameter d₄′. The diameters of the lumens,especially that of the lumen located at or near distal end 312, shouldbe large enough to not restrict the flow of the working fluid withinthem. Of course, any number of lumens may be provided depending on therequirements of the user.

[0246]FIG. 29 shows the connection between two adjacent inlet lumens 296and 300. A joint 314 is shown coupling the two lumens. The constructionof the joint may be by way of variations in stress, hardening, etc.

[0247] An advantage to this alternative embodiment arises from thesmaller diameters of the distal segments. The heat transfer element ofFIG. 28 may be placed in smaller workspaces than the heat transferelement of FIG. 27. For example, a treatment for brain trauma mayinclude placement of a cooling device in the internal carotid artery ofa patient. As noted above, the common carotid artery feeds the internalcarotid artery. In some patients, the heat transfer element of FIG. 27may not fit in the internal carotid artery. Similarly, the first coilsegment of the heat transfer element in FIG. 28 may not easily fit inthe internal carotid artery, although the second, third, and fourthsegments may fit. Thus, in the embodiment of FIG. 28, the first coilsegment may remain in the common carotid artery while the segments ofsmaller diameter (the second, third, and fourth) may be placed in theinternal carotid artery. In fact, in this embodiment, D_(c1) may belarge, such as 5-6 mm. The overall length of the heat transfer element286 may be, e.g., about 20 to 25 cm. Of course, such considerations playless of a role when the device is placed in a large vein such as theinferior vena cava.

[0248] An additional advantage was mentioned above. The surface area ofthe alternative embodiment of FIG. 28 may be substantially larger thanthat of the embodiment of FIG. 27, resulting in significantly enhancedheat transfer. For example, the enhancement in surface area may besubstantial, such as up to or even more than three times compared to thesurface area of the device of the application incorporated by referenceabove. An additional advantage of both embodiments is that the helicalrounded shape allows atraumatic insertion into cylindrical cavities suchas, e.g., arteries.

[0249] The embodiment of FIG. 28 may result in an Nu from 1 up to about50.

[0250]FIG. 30 shows a second alternative embodiment of the deviceemploying surface features rather than overall shape to induceturbulence. In particular, FIG. 30 shows a heat transfer element 314having an inlet lumen (not shown) and an outlet inflatable lumen 328having four segments 316, 318, 320, and 330. Segment 346 is adjacent aproximal end 326 and segment 330 is adjacent a distal end 322. Thesegments are arranged having reducing radii in the direction of theproximal end to the distal end. In a manner similar to that of theembodiment of FIG. 28, the feature of reducing radii allows insertion ofthe heat transfer element into small work places such as small arteries.

[0251] Heat transfer element 314 has a number of surface features 324disposed thereon. The surface features 324 may be constructed with,e.g., various hardening treatments applied to the heat transfer element314, or alternatively by injection molding. The hardening treatments mayresult in a wavy or corrugated surface to the exterior of heat transferelement 314. The hardening treatments may further result in a wavy orcorrugated surface to the interior of heat transfer element 314. FIG. 31shows a variation of this embodiment, in which a fabrication process isused which results in a spiral or helical shape to the surface features.

[0252] The embodiment of FIG. 30 may result in an Nu of about 1 to 50.

[0253] In another variation of this embodiment, shown in FIG. 33, a heattransfer element 356 employs a plurality of protrusions 360 on outletlumen 358 which surrounds an inlet lumen 364. In particular, FIG. 33 isa cut-away perspective view of an alternative embodiment of a heattransfer element 356. A working fluid is circulated through an inletlumen 362 to a distal tip of the heat transfer element 356 therebyinflating the heat transfer element 356. The working fluid thentraverses an outlet coaxial lumen 366 in order to transfer heat from theexterior surface 358 of the heat transfer element 356. The insidestructure of the heat transfer element 356 is similar to the exteriorstructure in order to induce turbulent flow of the working fluid.

[0254] An external surface 358 of the inflatable heat transfer element356 is covered with a series of staggered protrusions 360. The staggerednature of the protrusions 360 is readily seen with reference to FIG. 34which is a transverse cross-sectional view of an inflated heat transferelement taken along the line 8-8 in FIG. 33. In order to induce freestream turbulence, the height, d_(p), of the staggered protrusions 360is greater than the thickness of the boundary layer which would developif a smooth heat transfer element had been introduced into the bloodstream. As the blood flows along the external surface 358, it collideswith one of the staggered protrusions 360 and a turbulent flow iscreated. As the blood divides and swirls along side of the firststaggered protrusion 360, it collides with another staggered protrusion360 within its path preventing the re-lamination of the flow andcreating yet more turbulence. In this way, the velocity vectors arerandomized and free stream turbulence is created. As is the case withthe other embodiments, this geometry also induces a turbulent effect onthe internal coolant flow.

[0255] The embodiment of FIG. 33 may result in an Nu of about 1 to 50.

[0256] Of course, other surface features may also be used which resultin turbulence in fluids flowing past them. These include spirals,helices, protrusions, various polygonal bodies, pyramids, tetrahedrons,wedges, etc.

[0257] In some situations, an enhanced surface area alone, without thecreation of additional turbulence, may result in sufficient heattransfer to cool the blood. Referring to FIG. 32, a heat transferelement 332 is shown having an inlet lumen 334 and an outlet lumen 336.The inlet lumen 334 provides a working fluid to the heat transferelement 332 and outlet lumen 336 drains the working fluid from the same.The functions may, of course, be reversed. The heat transfer element 332is further divided into five segments, although more or less may beprovided as dictated by requirements of the user. The five segments inFIG. 32 are denoted segments 338, 340, 342, 344, and 346. In FIG. 32,the segment 338 has a first and largest radius R₁, followed bycorresponding radii for segments 340, 342, 344, and 346. Segment 346 hasa second and smallest radius. The length of the segment 338 is L₁,followed by corresponding lengths for segments 340, 342, 344, and 346.

[0258] A purely tapered (nonsegmented) form may replace the taperedsegmental form, but the former may be more difficult to manufacture. Ineither case, the tapered form allows the heat transfer element 332 to bedisposed in small arteries, i.e., arteries with radii smaller than R₁. Asufficient surface area is thus afforded even in very small arteries toprovide the required heat transfer.

[0259] The surface area and thus the size of the device should besubstantial to provide the necessary heat transfer. Example dimensionsfor a three-segmented tapered form may be as follows: L₁=10 cm, R₁=2.5mm; L₂=10 cm, R₂=1.65 mm, L₃=5 cm, R₃=1 mm. Such a heat transfer elementwould have an overall length of 25 cm and a surface area of 3×10⁻⁴ m².

[0260] The embodiment of FIG. 32 results in an enhancement of the heattransfer rate of up to about 300% due to the increased surface area Salone.

[0261] A variation of the embodiment of FIG. 32 includes placing atleast one turbulence-inducing surface feature within the interior of theoutlet lumen 336. This surface feature may induce turbulence in theworking fluid, thereby increasing the convective heat transfer rate inthe manner described above.

[0262] Another variation of the embodiment of FIG. 32 involves reducingthe joint diameter between segments (not shown ). For example, theinflatable material may be formed such that joints 348, 350, 352, and354 have a diameter only slightly greater than that of the inlet lumen334. In other words, the heat transfer element 332 has a tapered“sausage” shape.

[0263] In all of the embodiments, the inflatable material may be formedfrom seamless and nonporous materials which are therefore impermeable togas. Impermeability can be particularly important depending on the typeof working fluid which is cycled through the heat transfer element. Forexample, the inflatable material may be latex or other such rubbermaterials, or alternatively of any other material with similarproperties under inflation. The flexible material allows the heattransfer element to bend, extend and compress so that it is more readilyable to navigate through tiny blood vessels. The material also providesfor axial compression of the heat transfer element which can limit thetrauma when the distal end of the heat transfer element 272 abuts ablood vessel wall. The material should be chosen to toleratetemperatures in the range of −1° C. to 37° C., or even higher in thecase of blood heating, without a loss of performance.

[0264] It may be desirable to treat the surface of the heat transferelement to avoid clot formation because the heat transfer element maydwell within the blood vessel for extended periods of time, such as24-48 hours or even longer. One means by which to prevent thrombusformation is to bind an antithrombogenic agent to the surface of theheat transfer element. For example, heparin is known to inhibit clotformation and is also known to be useful as a biocoating.

[0265] Referring back to FIG. 27, an embodiment of the method of theinvention will be described. A description with reference to the otherembodiments is analogous. A guide catheter or wire may be disposed up toor near the area to be cooled or heated. The case of a guide catheterwill be discussed here. The heat transfer element may be fed through theguide catheter to the area. Alternatively, the heat transfer element mayform a portion of the guide catheter. A portion of the interior of theguide catheter may form, e.g., the return lumen for the working fluid.In any case, the movement of the heat transfer element is madesignificantly more convenient by the flexibility of the heat transferelement as has been described above.

[0266] Once the heat transfer element 272 is in place, a working fluidsuch as saline or other aqueous solution may be circulated through theheat transfer element 272 to inflate the same. Fluid flows from a supplycatheter into the inlet lumen 276. At the distal end 280 of the heattransfer element 272, the working fluid exits the inlet lumen 276 andenters the outlet lumen 274.

[0267] In the case of the embodiment of FIG. 30, for which thedescription of FIG. 33 is analogous, the working fluid exits the inletlumen and enters an outlet inflatable lumen 328 having segments 316,318, 320, and 330. As the working fluid flows through the outlet lumen328, heat is transferred from the exterior surface of the heat transferelement 314 to the working fluid. The temperature of the externalsurface may reach very close to the temperature of the working fluidbecause the heat transfer element 314 is constructed from very thinmaterial.

[0268] The working fluids that may be employed in the device includewater, saline or other fluids which remain liquid at the temperaturesused. Other coolants, such as freon, undergo nucleated boiling and maycreate turbulence through a different mechanism. Saline is a safecoolant because it is non-toxic and leakage of saline does not result ina gas embolism which may occur with the use of boiling refrigerants.

[0269] By enhancing turbulence in the coolant, the coolant can bedelivered to the heat transfer element at a warmer temperature and stillachieve the necessary heat transfer rate. In particular, the enhancedheat transfer characteristics of the internal structure allow theworking fluid to be delivered to the heat transfer element at lower flowrates and lower pressures. This is advantageous because high pressuresmay stiffen the heat transfer element and cause the same to push againstthe wall of the vessel, thereby shielding part of the heat transfer unitfrom the blood. Such pressures are unlikely to damage the walls of thevessel because of the increased flexibility of the inflated device. Theincreased heat transfer characteristics allow the pressure of theworking fluid to be delivered at pressures as low as 5 atmospheres, 3atmospheres, 2 atmospheres or even less than 1 atmosphere.

[0270] In a preferred embodiment, the heat transfer element creates aturbulence intensity greater than 0.05 in order to create the desiredlevel of turbulence in the entire blood stream during the whole cardiaccycle. The turbulence intensity may be greater than 0.055, 0.06, 0.07 orup to 0.10 or 0.20 or even greater.

[0271] As shown in FIG. 35, in another embodiment of the invention thecooling apparatus 368 of the present invention includes a flexiblemultilumen catheter 370, an inflatable balloon 372, and a plurality ofblood flow passageways 16 through the balloon 372. The balloon 372 isshown in an inflated state, in a selected position in a common carotidartery CC.

[0272] The balloon 372 is attached near a distal end of the flexiblecatheter 370. The catheter 370 can have at least a cooling fluid supplylumen 380 and a cooling fluid return lumen 382, with the cooling fluidsupply lumen 380 preferably being located substantially within thecooling fluid return lumen 382. The catheter 370 can also have aguidewire lumen 384, for the passage of a guidewire 386, as is known inthe art.

[0273] The balloon 372 can be formed from a flexible material, such as apolymer. The balloon 372 can be constructed to assume a substantiallycylindrical shape when inflated, with a proximal aspect 374 and a distalaspect 378. The balloon 372 can have a plurality of tubular shaped bloodflow passageways 376 formed therethrough, from the proximal aspect 374to the distal aspect 378. The tubular walls of the passageways 376constitute a heat transfer surface, for transferring heat from the bloodto the cooling fluid. The flexible material of the tubular passageways376 can be, at least in part, a metallized material, such as a filmcoated with a thin metal layer, either internally, externally, or both,to aid in heat transfer through the passageway walls. Alternatively, thetubular passageways 376 can be constructed of a metal-loaded polymerfilm. Further, the remainder of the balloon 372 can be coated with athin metallized layer, either internally, externally, or both, or ametal-loaded polymer film. The proximal aspect 374 and the distal aspect378 of the balloon can also constitute a heat transfer surface, fortransferring heat from the blood to the cooling fluid. The guidewirelumen 384 of the catheter 370 can also pass through the balloon 372,from the proximal aspect 374 to the distal aspect 378.

[0274] As shown in FIG. 36, each tubular passageway 376 has a proximalport 388 in a proximal face 390 on the proximal aspect 374 of theballoon 372, and a distal port 392 in a distal face 394 on the distalaspect 378 of the balloon 372. A cooling fluid supply port 396 near thedistal end of the cooling fluid supply lumen 380 supplies chilled salinesolution from a chiller (not shown) to the interior of the balloon 372,surrounding the blood flow passageways 376. A cooling fluid return port398 in the cooling fluid return lumen 382 returns the saline solutionfrom the interior of the balloon 372 to the chiller. Relative placementof the cooling fluid ports 396, 398 can be chosen to establish flowcounter to the direction of blood flow, if desired.

[0275]FIG. 37 shows the proximal aspect 402 of the balloon 372 and givesa view through the blood flow passageways 376, illustrating the generalarr angement of the blood flow passageways 376, cooling fluid supplylumen 380, cooling fluid return lumen 382, and guidewire lumen 384,within the outer wall 400 of the balloon 372.

[0276]FIG. 38 is a side elevation view of the apparatus 368, with apartial longitudinal section through the balloon wall 400, showing onepossible arrangement of the cooling fluid supply port 396 and thecooling fluid return port 398 within the balloon 372.

[0277] In practice, the balloon 372, in a deflated state, is passedthrough the vascular system of a patient on the distal end of thecatheter 370, over the guidewire 386. Placement of the guidewire 386 andthe balloon 372 can be monitored fluoroscopically, as is known in theart, by use of radiopaque markers (not shown) on the guidewire 386 andthe balloon 372. When the balloon 372 has been positioned at a desiredlocation in the feeding artery of a selected organ, such as in thecommon carotid artery feeding the brain, fluid such as saline solutionis supplied through the cooling fluid supply lumen 380. This fluidpasses through the cooling fluid supply port 396 into the interior ofthe balloon 372, surrounding the tubular passageways 376, to inflate theballoon 372. Although the balloon 372 can be formed to assume asubstantially cylindrical shape upon unconstrained inflation, theballoon 372 will essentially conform to the shape of the artery withinwhich it is inflated. As the balloon 372 inflates, the blood flowpassageways 376 open, substantially assuming the tubular shape shown.

[0278] When the balloon 372 has been properly inflated, blood continuesto flow through the feeding artery CC by flowing through the blood flowpassageways 376, as indicated, for example, by the arrows in FIG. 35.The size and number of the blood flow passageways 376 are designed toprovide a desired amount of heat transfer surface, while maintaining asuitable amount of blood flow through the feeding artery CC. Return flowto the chiller can be established, to allow flow of cooling fluidthrough the cooling fluid return port 398 and the cooling fluid returnlumen 382 to the chiller. This establishes a continuous flow of coolingfluid through the interior of the balloon 372, around the blood flowpassageways 376. The return flow is regulated to maintain the balloon372 in its inflated state, while circulation of cooling fluid takesplace. The saline solution is cooled in the chiller to maintain adesired cooling fluid temperature in the interior of the balloon 372, toimpart a desired temperature drop to the blood flowing through thetubular passageways 376. This cooled blood flows through the feedingartery to impart the desired amount of cooling to the selected organ.Then, cooling fluid can be evacuated or released from the balloon 372,through the catheter 370, to deflate the balloon 372, and the apparatus368 can be withdrawn from the vascular system of the patient.

[0279] Temperature Sensing

[0280] A guidewire may also be employed to assist in installing thedevice. The tip of the guidewire may contain or be part of a temperaturemonitor. The temperature monitor may be employed to measure thetemperature upstream or downstream of the heat transfer element andcatheter, depending on the direction of blood flow relative to thetemperature monitor. The temperature monitor may be, e.g., athermocouple or thermistor.

[0281] An embodiment of the invention may employ a thermocouple which ismounted on the end of the guidewire. For the temperatures considered inblood heating or cooling, most of the major thermocouple types may beused, including Types T, E, J, K, G, C, D, R, S, B.

[0282] In an alternative embodiment, a thermistor may be used which isattached to the end of the guidewire. Thermistors arethermally-sensitive resistors whose resistance changes with a change inbody temperature. The use of thermistors may be particularlyadvantageous for use in temperature-monitoring of blood flow pastcooling devices because of their sensitivity. For temperature monitoringof body fluids, thermistors that are mostly commonly used include thosewith a large negative temperature coefficient of resistance (“NTC”).These should ideally have a working temperature range inclusive of 25°C. to 40° C. Potential thermistors that may be employed include thosewith active elements of polymers or ceramics. Ceramic thermistors may bemost preferable as these may have the most reproducible temperaturemeasurements. Most thermistors of appropriate sizes are encapsulated inprotective materials such as glass. The size of the thermistor, forconvenient mounting to the guidewire and for convenient insertion in apatient's vasculature, may be about or less than 15 mils. Largerthermistors may be used where desired. Of course, various othertemperature-monitoring devices may also be used as dictated by the size,geometry, and temperature resolution desired.

[0283] A signal from the temperature monitoring device may be fed backto the source of working fluid to control the temperature of the workingfluid emerging therefrom. In particular, a catheter may be connected toa source of working fluid. A proximal end of a supply lumen defined by asupply tube is connected at an output port to the source of workingfluid. The return lumen defined by a return tube is similarly connectedat an input port to the source of working fluid. The source of workingfluid can control the temperature of the working fluid emerging from theoutput port. A signal from a circuit may be inputted to the source ofworking fluid at an input. The signal from the circuit may be from thethermocouple, or may alternatively be from any other type oftemperature-monitoring device, such as at the tip of the guidewire.

[0284] The signal may advantageously be employed to alter thetemperature, if necessary, of the working fluid from the source. Forexample, if the temperature-monitoring device senses that thetemperature of the blood flowing in the feeding vessel of the patient'svasculature is below optimal, a signal may be sent to the source ofworking fluid to increase the temperature of the working fluid emergingtherefrom. The opposite may be performed if the temperature-monitoringdevice senses that the temperature of the blood flowing in the feedingvessel of the patient's vasculature is above optimal.

[0285] Methods of Use

[0286] Simultaneous Cooling and Heating

[0287]FIG. 39 is a schematic representation of an embodiment of theinvention being used to cool the body of a patient and to warm a portionof the body. The hypothermia apparatus shown in FIG. 39 includes a firstworking fluid supply 404, preferably supplying a chilled liquid such aswater, alcohol or a halogenated hydrocarbon, a first supply catheter 406and the cooling element 102. The first supply catheter 406 may have asubstantially coaxial construction. An inner lumen within the firstsupply catheter 406 receives coolant from the first working fluid supply404. The coolant travels the length of the first supply catheter 406 tothe cooling element 102 which serves as the cooling tip of the catheter.At the distal end of the cooling element 102, the coolant exits theinsulated interior lumen and traverses the length of the cooling element102 in order to decrease the temperature of the cooling element 102. Thecoolant then traverses an outer lumen of the first supply catheter 406so that it may be disposed of or recirculated. The first supply catheter406 is a flexible catheter having a diameter sufficiently small to allowits distal end to be inserted percutaneously into an accessible veinsuch as the external jugular vein of a patient as shown in FIG. 39. Thefirst supply catheter 406 is sufficiently long to allow the coolingelement 102 at the distal end of the first supply catheter 406 to bepassed through the vascular system of the patient and placed in thesuperior vena cava 110, inferior vena cava (not shown), or other suchvein

[0288] The method of inserting the catheter into the patient and routingthe cooling element 102 into a selected vein is well known in the art.Percutaneous placement of the heat transfer element 102 into the jugularvein is accomplished directly, since the jugular vein is close to thesurface. The catheter would reside in the internal jugular and into thesuperior vena cava or even the right atrium.

[0289] Although the working fluid supply 404 is shown as an exemplarycooling device, other devices and working fluids may be used. Forexample, in order to provide cooling, freon, perfluorocarbon, water, orsaline may be used, as well as other such coolants.

[0290] The cooling element can absorb up to or more than 300 Watts ofheat from the blood stream, resulting in absorption of as much as 100Watts, 150 Watts, 170 Watts or more from the brain.

[0291]FIG. 39 also shows a heating element 410, shown as a heatingblanket. Heating blankets 410 generally are equipped with forcedwarm-air blowers that blow heated air through vents in the blanket in adirection towards the patient. This type of heating occurs through thesurface area of the skin of the patient, and is partially dependent onthe surface area extent of the patient. As shown in FIG. 39, the heatingblanket 410 may cover most of the patient to warm and provide comfort tothe patient. The heating blanket 410 need not cover the face and head ofthe patient in order that the patient may more easily breathe.

[0292] The heating blanket 410 serves several purposes. By warming thepatient, vasoconstriction is avoided. The patient is also made morecomfortable. For example, it is commonly agreed that for every onedegree of core body temperature reduction, the patient will continue tofeel comfortable if the same experiences a rise in surface area (skin)temperature of five degrees. Spasms due to total body hypothermia may beavoided. Temperature control of the patient may be more convenientlyperformed as the physician has another variable (the amount of heating)which may be adjusted.

[0293] As an alternative, the warming element may be any of the heatingmethods proposed in U.S. patent application Ser. No. 09/292,532, filedon Apr. 15, 1999, and entitled “Isolated Selective Organ Cooling Methodand Apparatus”, and incorporated by reference above.

[0294] Referring now to FIG. 40 is a schematic representation of anembodiment of the invention is shown, in a selective cooling version,being used to cool the brain of a patient, and to warm the bloodreturning from the brain in the jugular vein. The selective organhypothermia apparatus shown in FIG. 40 includes a first working fluidsupply 420, preferably supplying a chilled liquid such as water, alcoholor a halogenated hydrocarbon, a first supply catheter 418 and thecooling element 102. The first supply catheter 418 has a coaxialconstruction. An inner coaxial lumen within the first supply catheter418 receives coolant from the first working fluid supply 420. Thecoolant travels the length of the first supply catheter 418 to thecooling element 102 which serves as the cooling tip of the catheter. Atthe distal end of the cooling element 102, the coolant exits theinsulated interior lumen and traverses the length of the cooling element102 in order to decrease the temperature of the cooling element 102. Thecoolant then traverses an outer lumen of the first supply catheter 418so that it may be disposed of or recirculated. The first supply catheter418 is a flexible catheter having a diameter sufficiently small to allowits distal end to be inserted percutaneously into an accessible arterysuch as the femoral artery of a patient as shown in FIG. 40. The firstsupply catheter 418 is sufficiently long to allow the cooling element102 at the distal end of the first supply catheter 418 to be passedthrough the vascular system of the patient and placed in the internalcarotid artery or other small artery. The method of inserting thecatheter into the patient and routing the cooling element 102 into aselected artery is well known in the art.

[0295] Although the working fluid supply 420 is shown as an exemplarycooling device, other devices and working fluids may be used. Forexample, in order to provide cooling, freon, perfluorocarbon, water, orsaline may be used, as well as other such coolants.

[0296] The cooling element can absorb or provide over 75 Watts of heatto the blood stream and may absorb or provide as much as 100 Watts, 150Watts, 170 Watts or more. For example, a cooling element with a diameterof 4 mm and a length of approximately 10 cm using ordinary salinesolution chilled so that the surface temperature of the heat transferelement is approximately 5° C. and pressurized at 2 atmospheres canabsorb about 100 Watts of energy from the bloodstream. Smaller geometryheat transfer elements may be developed for use with smaller organswhich provide 60 Watts, 50 Watts, 25 Watts or less of heat transfer.

[0297]FIG. 40 also shows a second working fluid supply 416, preferablysupplying a warm liquid such as water, a second supply catheter 414 andthe warming element 412, which can be similar or identical to thecooling element 102. The second supply catheter 414 has a coaxialconstruction. An inner coaxial lumen within the second supply catheter414 receives warm fluid from the second working fluid supply 416. Thefluid travels the length of the second supply catheter 414 to thewarming element 412 which serves as the warming tip of the catheter. Atthe distal end of the warming element 412, the fluid exits the insulatedinterior lumen and traverses the length of the warming element 412 inorder to increase the temperature of the warming element 412. The fluidthen traverses an outer lumen of the second supply catheter 414 so thatit may be disposed of or recirculated. The second supply catheter 414 isa flexible catheter having a diameter sufficiently small to allow itsdistal end to be inserted percutaneously into an accessible vein such asthe left internal jugular vein of a patient as shown in FIG. 40.

[0298] As an alternative, the warming element 412 can be an electricalresistance heater controlled by a controller represented by item 416.

[0299] Percutaneous placement of the warming element 412 into thejugular vein is accomplished directly, since the jugular vein is closeto the surface. The catheter would reside in the internal jugular andinto the superior vena cava or even the right atrium. Jugular venouscatheters are known. As an alternative to warming of the blood in thejugular vein with a warming element 412, a warm saline solution can beinfused into the jugular vein from a saline supply 422, via anintravenous catheter 420, as shown in FIG. 41. This is advantageoussince saline drips are often necessary anyway as maintenance fluids(1000 to 2500 cc/day). As yet another alternative, warming can beapplied externally to the patient. The means of warming can be a heatingblanket applied to the whole body, or localized heating of veinsreturning from the organ being cooled. As an example, FIG. 42 shows aneck brace 426 being used to immobilize the head of the patient.Immobilization of the head can be necessary to prevent movement of thecooling element, or to prevent puncture of the feeding artery by thecooling element. The neck brace 426 can have one or more warmingelements 428 placed directly over the left and right internal jugularveins, to heat the blood flowing in the jugular veins, through the skin.The warming elements 428 can be warmed by circulating fluid, or they canbe electrical resistance heaters. Temperature control can be maintainedby a working fluid supply or controller 424.

[0300] One practice of the present invention is illustrated in thefollowing non-limiting example.

[0301] Exemplary Procedure

[0302] 1. The patient is initially assessed, resuscitated, andstabilized.

[0303] 2. The procedure may be carried out in an angiography suite orsurgical suite equipped with fluoroscopy.

[0304] 3. An ultrasound or angiogram of the superior vena cava andexternal jugular can be used to determine the vessel diameter and theblood flow; a catheter with an appropriately sized heat transfer elementcan be selected.

[0305] 5. After assessment of the veins, the patient is sterilelyprepped and infiltrated with lidocaine at a region where the femoralartery may be accessed.

[0306] 6. The external jugular is cannulated and a guide wire may beinserted to the superior vena cava. Placement of the guide wire isconfirmed with fluoroscopy.

[0307] 7. An angiographic catheter can be fed over the wire and contrastmedia injected into the vein to further to assess the anatomy ifdesired.

[0308] 8. Alternatively, the external jugular is cannulated and a10-12.5 french (f) introducer sheath is placed.

[0309] 9. A guide catheter is placed into the superior vena cava. If aguide catheter is placed, it can be used to deliver contrast mediadirectly to further assess anatomy.

[0310] 10. The cooling catheter is placed into the superior vena cavavia the guiding catheter or over the guidewire.

[0311] 11. Placement is confirmed if desired with fluoroscopy.

[0312] 12. Alternatively, the cooling catheter shaft has sufficientpushability and torqueability to be placed in the superior vena cavawithout the aid of a guide wire or guide catheter.

[0313] 13. The cooling catheter is connected to a pump circuit alsofilled with saline and free from air bubbles. The pump circuit has aheat exchange section that is immersed into a water bath and tubing thatis connected to a peristaltic pump. The water bath is chilled toapproximately 0° C.

[0314] 14. Cooling is initiated by starting the pump mechanism. Thesaline within the cooling catheter is circulated at 5 cc/sec. The salinetravels through the heat exchanger in the chilled water bath and iscooled to approximately 1° C.

[0315] 15. The saline subsequently enters the cooling catheter where itis delivered to the heat transfer element. The saline is warmed toapproximately 5-7° C. as it travels along the inner lumen of thecatheter shaft to the end of the heat transfer element.

[0316] 16. The saline then flows back through the heat transfer elementin contact with the inner metallic surface. The saline is further warmedin the heat transfer element to 12-15° C., and in the process, heat isabsorbed from the blood, cooling the blood to 30° C. to 35° C. Duringthis time, the patient may be warmed with an external heat source suchas a heating blanket.

[0317] 17. The chilled blood then goes on to chill the body. It isestimated that less than an hour will be required to cool the brain to30° C. to 35° C.

[0318] 18. The warmed saline travels back the outer lumen of thecatheter shaft and is returned to the chilled water bath where the sameis cooled to 1° C.

[0319] 19. The pressure drops along the length of the circuit areestimated to be between 1 and 10 atmospheres.

[0320] 20. The cooling can be adjusted by increasing or decreasing theflow rate of the saline. Monitoring of the temperature drop of thesaline along the heat transfer element will allow the flow to beadjusted to maintain the desired cooling effect.

[0321] 21. The catheter is left in place to provide cooling for, e.g.,6-48 hours.

[0322] In another method of use, and referring to FIG. 43, analternative embodiment is shown in which the heat transfer element 102is disposed in the superior vena cava 110 from the axillary vein ratherthan from the external jugular. It is envisioned that the followingveins may be appropriate to percutaneously insert the heat transferelement: femoral, internal jugular, subclavian, and other veins ofsimilar size and position. It is also envisioned that the followingveins may be appropriate in which to dispose the heat transfer elementduring use: inferior vena cava, superior vena cava, femoral, internaljugular, and other veins of similar size and position.

[0323]FIG. 1 shows a cross-section of the heart in which the heattransfer element 102 is disposed in the superior vena cava 110. The heattransfer element 102 has rotating helical grooves 104 as well ascounter-rotating helical grooves 106. Between the rotating and thecounter-rotating grooves are bellows 108. It is believed that a designof this nature would enhance the Nusselt number for the flow in thesuperior vena cava by about 5 to 80.

[0324] Methods of use Employing Thermoregulatory Drugs

[0325] The above description discloses mechanical methods of rewarming apatient, or portions of a patient, to minimize the deleteriousconsequences of total body hypothermia. Another procedure which may beperformed, either contemporaneous with or in place of mechanicalwarming, is the administration of anti-vasoconstriction andanti-shivering drugs. Such drugs minimize the effect of vasoconstrictionwhich may otherwise hinder heat transfer and thus cooling of thepatient. In general, hypothermia tends to trigger aggressivethermoregulatory defenses in the human body. Such drugs also prohibitresponses such as shivering which may cause damage tocardiac-compromised patients by increasing their metabolic rate todangerous levels.

[0326] To limit the effectiveness of thermoregulatory defenses duringtherapeutic hypothermia, drugs that induce thermoregulatory tolerancemay be employed. A variety of these drugs have been discovered. Forexample, clonidine, meperidine, a combination of clonidine andmeperidine, propofol, magnesium, dexmedetomidine, and other such drugsmay be employed.

[0327] It is known that certain drugs inhibit thermoregulation roughlyin proportion to their anesthetic properties. Thus, volatile anesthetics(isoflurane, desflurane, etc.), propofol, etc. are more effective atinhibiting thermoregulation than opioids which are in turn moreeffective than midazolam and the central alpha agonists. It is believedthat the combination drug of clonidine and meperidine synergisticallyreduces vasoconstriction and shivering thresholds, synergisticallyreduces the gain and maximum intensity of vasoconstriction andshivering, and produces sufficient inhibition of thermoregulatoryactivity to permit central catheter-based cooling to 32° C. withoutexcessive hypotension, autonomic nervous system activation, or sedationand respiratory compromise.

[0328] These drugs may be particularly important given the rapid onsetof thermoregulatory defenses. For example, vasoconstriction may set inat temperatures of only ½ degree below normal body temperature.Shivering sets in only a fraction of a degree below vasoconstriction.

[0329] The temperature to which the blood is lowered may be such thatthermoregulatory responses are not triggered. For example,thermoregulatory responses may be triggered at a temperature of 1-1½degrees below normal temperature. Thus, if normal body temperature is37° C., thermoregulatory responses may set in at 35° C. Thermoregulatorydrugs may be used to lower the temperature of the thermoregulatorytrigger threshold to 33° C. Use of the heating blankets described abovemay allow even further cooling of the patient. For example, to lower thepatient's temperature from 33° C. to 31° C., a 2° C. temperaturedifference, a 2 times 5° C. or 10° C. rise is surface temperature may beemployed on the skin of the patient to allow the patient to not “feel”the extra 2° C. cooling.

[0330] A method which combines the thermoregulatory drug methodology andthe heating blanket methodology is described with respect to FIG. 44.This figure is purely exemplary. Patients' normal body temperaturesvary, as do their thermoregulatory thresholds.

[0331] As shown in FIG. 44, the patient may start with a normal bodytemperature of 37° C. and a typical thermoregulatory threshold of 35° C.(step 432). In other words, at 35° C., the patient would begin to shiverand vasoconstrict. A thermoregulatory drug may be delivered (step 434)to suppress the thermoregulatory response, changing the thresholdtemperature to, e.g., 35° C. This new value is shown in step 436. Theheat transfer element may then be placed in a high flow vein, such asthe superior or inferior vena cavae or both (step 438). Cooling mayoccur to lower the temperature of the blood (step 440). The cooling maybe in a fashion described in more detail above. The cooling results inthe patient undergoing hypothermia and achieving a hypothermictemperature of, e.g., 33° C. (step 442). More cooling may be performedat this stage, but as the thermoregulatory threshold has only beensuppressed to 33° C. (step 442), shivering and vasoconstriction woulddeleteriously result. This may complete the procedure. Alternatively, anadditional drug therapy may be delivered to further lower thethermoregulatory threshold.

[0332] An alternate way to lower the thermoregulatory threshold is touse a heating blanket. As noted above, a common rule-of-thumb is that apatient's comfort will stay constant, even if their body temperature islowered 1° C., so long as a heating blanket, 5° C. warmer than theirskin, is applied to a substantial portion of the surface area of thepatient (step 444). For a 2° C.-body temperature reduction, a 10° C.(warmer than the skin temperature) blanket would be applied. Of course,it is also known that blankets warmer than about 42° C. can damagepatient's skins, this then being an upper limit to the blankettemperature. The patient's body temperature may then continue to belowered by use of a heating blanket. For each 1° C. reduction in bodytemperature (step 446), the heating blanket temperature may be raised 5°C. (step 448). After each reduction in body temperature, the physicianmay decide whether or not to continue the cooling process (step, 450).After cooling, other procedures may be performed if desired (step 452)and the patient may then be rewarmed (step 454).

[0333] It is important to note that the two alternate methods ofthermoregulatory response reduction may be performed independently. Inother words, either thermoregulatory drugs or heating blankets may beperformed without the use of the other. The flowchart given in FIG. 44may be used by omitting either step 434 or steps 444 and 448.

[0334] Vasoconstrictive Therapies

[0335]FIG. 2 showed the more rapid response of the high blood floworgans to hypothermia than that of the peripheral circulation. Thisresponse may be maintained or enhanced by applying, as an alternativemethod of performing hypothermia, a cooling blanket rather than aheating blanket. The cooling blanket may serve to vasoconstrict thevessels in the peripheral circulation, further directing blood flowtowards the heart and brain.

[0336] An alternate method of performing the same function is to provideseparate vasoconstrictive drugs which affect the posterior hypothalamusin such a way as to vasoconstrict the peripheral circulation whileallowing heart and brain circulation to proceed unimpeded. Such drugsare known and include alpha receptor type drugs. These drugs, as well asthe cooling blankets described above, may also enhance counter-currentexchange, again forcing cooling towards the heart and brain. Generally,any drug or cooling blanket that provides sufficient cooling to initiatea large scale cutaneous peripheral vasoconstrictive response would becapable of forcing the cooling blood flow towards the brain and heart(i.e., the “central” volumes). In this application, the term “peripheralcirculation” or “peripheral vasculature” refers to that portion of thevasculature serving the legs, arms, muscles, and skin.

[0337] Antishiver Drugs and Regimens

[0338] Other thermoregulatory drugs are now described. Meperidine is ananalgesic of the phenyl piperdine class that is known to bind to theopiate receptor. Meperidine is also used to treat shivering due topost-operative anesthesia and hypothermia. Meperidine can also treatrigors associated with the administration of amphotericin B.

[0339] Meperidine can also be used to control shivering when hypothermiais induced clinically. During periods of ischemia, such as occurs duringa stroke or heart attack, hypothermia can protect the tissue fromdamage. It is important to be able to cool patients with out inducing ageneral anesthetic condition requiring intubation. To cool consciouspatients requires very high doses of meperidine. Cooling of patients canbe accomplished by the above noted methods such as cooling blankets (airor water) or alcohol bathing. Cooling can also be accomplished by bodycavity lavage (bladder, stomach, colon, peritoneal). The most efficientway to cool patients, as noted above for therapeutic purposes, is usingan intravascular catheter. An intravascular cooling catheter has a heatexchange region that is responsible for exchanging heat with the blood.Absorption of heat from the blood by the heat exchange region results incooling of the body. Causing mixing, or turbulence, on, or near, theheat exchange region, enhances heat transfer by intravascular methods.The heat exchanger of the intravascular catheter can have features thatinduce turbulence or mixing.

[0340] Shivering is regulated by the hypothalamus of the brain. Thehypothalamus regulates body temperature in general by controlling heatproduction and heat loss. Heat production above the base metabolic levelis produced through shivering, while heat loss is prevented byvasoconstriction, which decreases blood flow to the skin/periphery. Thenormothermic set point of the hypothalamus is approximately 37° C. Whenthe body is cooled a threshold is reached at which vasoconstriction andshivering occur. Vasoconstriction occurs approximately 0.5-1.0° C. belowthe set point, with shivering occurring 1.0-1.5° C. below the set point.The intensity of shivering increases proportionally with the differencefrom the threshold up to a maximum intensity. Meperidine lowers thethreshold at which shivering occurs, but it does not have much effect onthe gain and maximum intensity. The reduction of the shivering thresholdis proportional to the serum concentration of meperidine, such thatgreater serum concentrations cause a greater reduction in the threshold.Meperidine is believed to possess special antishivering effects, inparticular because it decreases the shivering threshold twice as much asthe vasoconstriction threshold. In addition, it prevents or managesshivering better than equianalgesic doses of other opioids.

[0341] Meperidine's antishivering effects (lowering of the shiveringthreshold) may not be related to binding of the opiate receptor.Meperidine is known to have numerous non-opioid effects such asanticholinergic action and local anesthetic properties. Further, theantishivering effects produced by meperidine are not antagonized bynalaxone, an opiate receptor antagonist. In addition, other opiates suchas morphine, pentazocine, and nalbuphine have less or no antishiveringactivity. Referring now to FIG. 45, the meperidine molecule 456 isstructurally very different from the morphine 458 in FIG. 46 or morphinederivatives, which may help explain the different effects.

[0342] Meperidine usage has a number of undesirable side effects, andmany are related to the affinity for the opiate receptor. The mostserious is respiratory sedation, which can result in death, and may berelated to affinity for the delta opiate receptor. It has been shownthat blocking the delta opiate receptor with an antagonist can reduce oreliminate opioid induced respiratory sedation. In addition, meperidineis metabolized in the liver by n-demethylation, which produces themetabolite nor-meperidine. Nor-meperidine is known to have centralnervous system toxicity and can cause seizures. Meperidine cannot beused in patients with renal insufficiency or kidney failure due to arapid build up of the normeperidine metabolite. In addition, meperidinecannot be used in patients taking monoamine oxidase inhibitors, due tocomplications such as convulsions and hyperpyrexia.

[0343] Prodines (alpha and beta) (see FIGS. 47 and 48, molecules 460 and462) are structurally very similar to meperidine. They too bind to theopiate receptor, though with greater affinity. Unlike meperidine,prodines have chirality. Chiral molecules have at least one asymmetricatomic center that causes the mirror image of the base molecule to benon-superimposable on base molecule. Each species, the base molecule andthe mirror image, is referred to as an enantiomer.

[0344] Chiral molecules are optically active meaning each enatiomer canrotate a plane of polarized light equal but opposite directions,clockwise and counter clockwise, plus and minus. Thus if one enantiomerrotates a plane of polarized light +10 degrees {(+) enantiomer}, theopposite enantiomer will rotate light −10 degrees {(−) enantiomer)}. Forexample, the two prodines, known as alpha and beta, differ in theposition of the 3-methyl group. A chiral atomic center exists at thecarbon to which the 3-methyl group is bound and results in the variousenantiomeric species. The chemical reactions that produce chiralmolecules often produce racemic mixtures, or mixtures that containfractions of each enantiomer. A racemic mixture that contains equalproportions of each enatiomer is optically inactive.

[0345] Binding to the opiate receptor is known to be stereoselective.This means that one enantiomer has much greater affinity for thereceptor than the other enantiomer. For example, the (−) isomer ofmorphine has much greater affinity for the opiate receptor than the (+)isomer. In the case of alpha an d beta prodine, the (+) isomer has muchgreater affinity for the receptor than the (−) isomer.

[0346] It is reasonable to assume that the prodines have anti-shivereffects similar to meperidine due to their structural similarity. Thisis a reasonable assumption because fentanyl (molecule 464 of FIG. 49),an opioid analgesic that is also structurally related to meperidine,also has anti-shiver effects. Fentanyl, also has opiate related sideeffects such as respiratory sedation.

[0347] The ideal antishiver medication or regimen would have potentantishiver efficacy with little respiratory sedation or other sideeffects. One way to accomplish is to use meperidine, fentanyl, or otheropioids with antishiver effects, in combination with a delta opiatereceptor antagonist. Naltrindole or naltriben are competitiveantagonists at the delta receptor and can block the respiratory sedationcaused by fentanyl. Thus, inducing hypothermia in a conscious patientusing an intravascular cooling catheter would be accomplished using adrug regimen that included an opiate such as fentanyl or meperidine incombination with a delta receptor antagonist, such as naltrindole.

[0348] A molecule structurally similar to meperidine, but unable to bindto the opiate receptor or having antagonism at the opiate receptor,would likely possess anti-shiver effects, but not opiate relatedrespiratory sedation, since anti-shivering effects may be mediatedthrough a different receptor. This ideal anti-shiver molecule exists inthe form of the (−) isomer of alpha or beta prodine. The ratio of opiateefficacy (+/−) between the enantiomeric forms of alpha and beta prodineis at least 10 to 30 fold. Because of the structural similarity tomeperidine they would likely retain the antishiver efficacy. In ananalogous example, dextromethorphan is a morphine-based chemical that isa cough suppressant (antitussive). Dextromethorphan, which is the (+)methoxy enantiomer of (−) levorphanol, has retained the antitussiveeffects of morphine derivatives (i.e. (−) levorphanol), but lost otheropiate effects such as analgesia, respiratory sedation, and addiction.

[0349] In addition, the opiate receptor affinity of the (+) isomer ofalpha and beta prodine could also be interrupted. This can beaccomplished by adding a hydroxyl (particularly in the m position) tophenyl ring. This is particularly true of the potent opiate analgesicalpha-allylprodine, in which the 3-methyl is replaced with an allylgroup (see molecule 466 of FIG. 50). Further, the opiate activity of (+)betaprodine isomer can be significantly diminished by the substitutionof the 3-methyl group with an n-propyl or allyl group. Thesemodifications to the (+) isomers of the prodine molecules that inhibitopiate activity will not likely effect antishiver activity due to thestructural similarity to meperidine.

[0350] Cis-Picenadol, 1,3 dimethyl-4-propyl-4-hydroxyphenyl piperdine(cis 3-methyl, 4-propyl) is phenyl piperdine compound in which the (−)enantiomer has antagonist properties at the opiate receptor (seemolecules 468 and 470 of FIGS. 51 and 52). Due to the structuralsimilarity to meperidine, this (−) enantiomer may have anti-shiveractivity with little respiratory sedation. It is known that the racemicmixture of this opioid has a ceiling effect with respect to respiratorysedation when used in animals. This ceiling effect may make racemicpicenadol a better anti-shiver drug than meperidine. Finally, tramadol(molecule 472 of FIG. 53) may have an enantiomer that has reduced opiateactivity that could lower the shiver threshold.

[0351] Alpha prodine has been used as an analgesic in clinical medicine,marketed under the trade name Nisentil. The drug is supplied as aracemic mixture. It is possible to separate the racemic mixture into twopure isomers and use the (−) isomer as an antishiver medication. Such aseparation can be accomplished using high-performance liquidchromatography (HPLC) using a chiral stationary phase. One such chiralstationary phase is cellulose-based and is supplied as Chiralcel OD andChiralcel OJ.

[0352] A representative example of the use of the novel antishiver, orthreshold lowering, drugs or regimen, is a clinical procedure to inducehypothermia in a patient. The patient would first be diagnosed with anischemic injury, such as a stroke or heart attack. An intravascularcooling catheter or a cooling blanket would be applied to the patient.The patient would be given an intravenous injection of the novel antishiver drug, such as (−) alpha prodine. Alternatively the patient couldbe given meperidine or fentanyl in combination with a delta opiatereceptor antagonist. Buspirone could be given in combination with eitherof the above regimens because it is know to enhance the antishivereffects of meperidine. The patient would be cooled to 32-35° C. orlower. During the maintenance of cooling which could last 12-48 hours orlonger, doses of the antishiver drug or regimen would begin to maintaina certain plasma concentration. An infusion of the novel antishiver drugcould be used to maintain the plasma concentration. When the cooling wascomplete the patient would be rewarmed and the drugs discontinued.

[0353] Another ideal antishiver drug may be nefopam (molecule 474 ofFIG. 54). Nefopam is widely used as an analgesic, particularly outsidethe U.S. While it is not an analog of meperidine, it has similarstructural and conformational properties. For example it has a phenylgroup attached to a N-methyl ring, and the phenyl group prefers theequatorial position. Similar to meperidine, nefopam is known to preventpost-operative shivering and to prevent shivering related toAmphotericin B administration. However, nefopam has less respiratorydepression side effects, and is not metabolized into a neurotoxiccompound. Injectable nefopam is a racemic mixture. Analgesic activityresides in the (+) enantiomer. The (−) enantiomer may be a selectiveanti-shiver drug and superior to the racemic form. Combining nefopamwith intravascular catheter based cooling induction may allow forsuccessful implementation of therapeutic hypothermia.

[0354] It may also be desirable to use combinations of the compoundslisted above or combine them with other drugs that can reduce shiveringand lower the threshold. This may lower the doses needed for either drugand reduce side effects. For example, one could combine nefopam with (−)alpha-prodine, meperidine, thorazine, buspirone, clonidine, tramadol, orother medications to achieve the desired effect. The same combinationscould be used with (−) alpha-prodine. There are many other combinationsthat could be tried including combining three agents together. Thesecombinations can be used with endovascular or surface hypothermiainduction for therapeutic purposes.

[0355] Enzyme Temperature Dependence

[0356] The above devices and techniques, including those disclosed inthe applications incorporated by reference above, provide effectivecooling or heating of a fluid such as blood. The heating or cooling mayoccur either in the affected vessel or in a vessel in fluidcommunication with the affected vessel. In this disclosure, as notedabove, “fluid communication” between two vessels refers to a situationwhere one vessel either feeds or is fed by the other. One application ofthese devices and techniques is for clot lysis. However, other types ofenzyme activations may also be advantageously induced. The methoddisclosed below is applicable to other devices and techniques so long asthey are also capable of heating or cooling blood.

[0357] As noted above, enzymes have been delivered to patients in drugor intravenous form for clot lysing. These enzymes are in addition tonaturally occurring enzymes already in the blood plasma. The activity ofenzymes is at least partially adjusted by control of environmentaltemperature. A method according to an embodiment of the inventionselectively controls enzyme activity by controlling the temperature ofthe environment of the enzyme. This controlled enzyme activity allowsselective thrombolysis by selective vessel hypothermia in a mannerdescribed in more detail below.

[0358] Several experimental procedures have been reported on animals andclot preparations at various temperatures, as disclosed below, andappropriate temperature regimes for thrombolysis may be inferred withsome accuracy. However, the mechanisms by which enzyme environmentaltemperature controls thrombolysis are not yet well characterized.Disclosed below are several suggested mechanisms. These suggestedmechanisms are conjecture, and should not be construed as limiting, inany way, the method of the invention.

[0359] The suggested mechanisms rely to a certain extent on the knownmechanisms for fibrinolysis. In particular, plasminogen is the inertprecursor of plasmin. Plasmin is an enzyme that lyses clots, i.e.,cleaves peptide bonds in fibrin. Plasminogen binds to fibrin and, whenactivated by an appropriate enzyme, such as tPA, UK, SK, etc., convertsto plasmin. Plasminogen may also be activated in solution. Inhibitorssuch as α₂-antiplasmin moderate plasmin activity by inactivating plasminreleased from a fibrin surface almost instantaneously. α₂-antiplasmincan even inactivate plasmin bound to a fibrin surface, but this processrequires about 10 seconds.

[0360] One suggested mechanism concerns the action of the inhibitors.The activity of α₂-antiplasmin is lessened at low temperatures and thusis less effective at inactivating plasmin. In this case, more plasmin isavailable to lyse clots and thus fibrinolysis is enhanced.

[0361] A related effect is due to the effect of plasmin levels onplasminogen levels. Increased plasmin levels may lead to increasedplasminogen levels circulating in solution. Moreover, decreased activityof α₂-antiplasmin also leads to increased plasminogen levels becauseα₂-antiplasmin binds plasminogen, and less α₂-antiplasmin means less ofsuch binding.

[0362] Increased plasminogen levels also suggests several othermechanisms for clot lysing.

[0363] For example, plasmin cleaves single-chain urokinase (“scu-PA” or“pro-UK”) to form UK, i.e., pro-UK is a precursor to UK. Pro-UK, liketPA, cannot efficiently activate plasminogen in solution, but it canreadily activate plasminogen bound to fibrin. Thus, increasedplasminogen, together with the body's own UK or tPA, or similar enzymesprovided intravenously, may result in more localized lysing of fibrin,e.g., directly at the clot situs.

[0364] Another suggested mechanism results from increased plasminogen.UK can activate both plasminogen in solution and plasminogen bound tofibrin. Thus, increased plasminogen levels, together with the body's ownUK, or that provided intravenously, results in both localized lysing offibrin and enhanced activation of plasminogen in solution.

[0365] Another suggested mechanism results from the conjectured bond ofplasmin to fibrin. Plasmin may stay bound to fibrin for a longer periodin the hypothermic state. Thus, more time may be available to lyseclots, increasing overall fibrinolysis.

[0366] The hypothermic temperatures at which increased fibrinolysisoccurs have not been fully explored. However, it has been shown thatclot samples have benefited from temperatures of, e.g., 25° C. or below.For human patients, it is believed that temperatures of 30° C. to 32° C.may well be appropriate and advantageously employed in the method of theinvention.

[0367] In a related embodiment of the invention, the method may furtheremploy a step of rewarming the cooled organ from the low temperature of,e.g., 30° C. The temperature range for rewarming may be from about 20°C. to 37° C. depending on the patient, the condition, the hypothermictemperature, and so on. Rewarming has been shown to have a beneficialeffect in certain studies, perhaps by increasing the rate at which clotlysis occurs. In another related embodiment of the invention, the methodmay further employ temperature cycling the blood in the vessel from ahypothermic temperature to a rewarmed temperature. In this way, therewarming temperature regime is achieved repeatedly and thus so is theenhanced fibrinolysis.

EXAMPLE ONE (NON-DRUG)

[0368] Researchers have studied the effect of temperature onfibrinolysis in the context of drug studies. As part of these studies,control groups are investigated in which no drugs are introduced. In onesuch investigation using clot samples, clot lysis was investigated whilevarying clot temperatures in a range of 25° C. to 41° C. In the absenceof drugs, enhanced clot lysis was seen at the lower part of thetemperature range. It is believed that this study can be extended tohumans, and thus fibrinolytic activity can be enhanced at lowertemperatures.

EXAMPLE TWO (NON-DRUG)

[0369] In another non-drug study of the effect of temperature onfibrinolysis, clot lysis in dogs was investigated while varying clottemperatures in a range of 20° C. to 36° C. The dog's temperature waslowered from a normal temperature to a low temperature. A gradualrewarming period followed the low temperature period.

[0370] Enhanced clot lysis was observed at lower temperatures ascompared to higher temperatures. In particular, the maximum fibrinolyticactivity occurred in the early rewarming period, i.e., from 20° C. toabout 25° C. It is believed that this study can be extended to humans,and that fibrinolytic activity can be enhanced at lower temperatures,especially during periods of rewarming.

[0371] An advantage of all of these embodiments of the method is thatclot lysis can be achieved in a simple manner and without the need fordrugs. An additional advantage results from the reduced temperature ofthe blood which helps to protect the cells from ischemia at the sametime lysis is occurring. Thus, clot lysis and cooling occursimultaneously, providing an effective and aggressive dual therapy. Whendual therapies are employed, cooling catheters may be inserted in bothfemoral arteries for transit to the brain. One cooling catheter coolsthe brain, while the other cools the blood in the artery leading to theclot. The latter provides the beneficial effects noted above.

[0372] In some cases, of course, the nature or extent of the clot issuch that lysing may only occur with drug intervention. In these cases,thrombolytic drugs, such as those disclosed above, may be introduced toinduce the fibrinolysis.

[0373] These drugs are effective at treating the thrombus. However, itmay also be advantageous to cool the brain as a separate neuroprotectivemeasure. The effectiveness of both therapies is enhanced when applied assoon as possible. Thus, it is often desirable to apply both therapiessimultaneously. In this way, hypothermia is induced as a neuroprotectivemeasure, and may further induce clot lysing per se in the mannerdescribed above.

[0374] A difficulty with this approach is that the techniques areinterdependent. Drugs depend on enzymes for their activity, and enzymesare temperature-dependent. In fact, past studies have demonstrated thatthe enzyme activity of these specific thrombolytic drugs on clot samplesis temperature-dependent. In other words, their effect on clot orthrombus lysis varies over a temperature range. For typicaltemperature-specific enzymes, the greatest activity occurs at an optimaltemperature. The optimal temperature may be about 37° C. in the case ofknown thrombolytics, as this is the normal human body temperature.

[0375] Enzyme activity drastically reduces above certain temperatures asthe enzyme denatures and becomes inactive. At the opposite extreme,enzyme activity reduces below certain temperatures as the enzyme lacksthe energy necessary to couple to a substrate. Therefore, when the brainor other tissue is at a temperature different from normal bodytemperature, e.g., during hypothermia, an isoform of the enzyme ispreferably used which has an optimal working temperature at thehypothermic body temperature. In this disclosure, such an isoform whichis effective at a different temperature is said to have a “workingtemperature” at the different temperature or within a range of differenttemperatures.

[0376] In this disclosure, the term “isoform” of an enzyme is used asfollows. If a first enzyme catalyzes a reaction at a first temperature,and a different enzyme catalyzes the same reaction at a secondtemperature, then the different enzyme is an “isoform” of the firstenzyme within the meaning intended here.

[0377] For patients undergoing hypothermia, the physician may preferablyuse a low-temperature isoform; for patients whose temperatures have beenraised, the physician may preferably use a high-temperature isoform. Theform of the enzyme will preferably have an optimal activity curve at ornear the desired temperature. Known enzymes are described below,followed by a methodology for choosing enzymes which are not yet known.

EXAMPLE THREE (SK)

[0378] Researchers have investigated the effect of temperature on thefibrinolytic activity of an SK mixture. In one such effort, clots weretreated with a mixture of plasminogen (2 mg) and SK (100 IU) in a totalvolume of 15 ml PBS. The temperature of the clots was raised from 24° C.to 37° C. These researchers found that heating enhanced the fibrinolyticactivity. In other words, heating from a hypothermic temperature tonormal body temperature increased clot lysing for clots treated with SK.

[0379] It is believed that such general trends may be extended topatients without lack of accuracy. Patients may be provided with a drugsuch as streptokinase and may undergo hypothermia using, e.g., one ofthe devices or methods described above. In particular, a coolingcatheter may be placed in an artery supplying blood to a thrombosedvessel. The catheter may include a separate lumen through which the SKmixture may be delivered. A coolant or working fluid may be supplied tothe cooling catheter, causing the same to cool and to cool the bloodadjacent a heat transfer element located at a distal tip of the coolingcatheter. This cooling step may include the step of inducing turbulencein the blood flowing through the vessel and/or in the working fluid. SKmay be delivered through the separate drug delivery lumen. The patientmay then be rewarmed as the SK is delivered. The rewarming step may beaccomplished by passing a warm saline solution as the working fluid.

EXAMPLE FOUR (TPA)

[0380] Researchers have also investigated the effect of temperature onthe fibrinolytic activity of tPA. Clots were treated with 2.5 μg/ml tPAand incubated at various temperatures (e.g., 37° C., 25° C., 10° C., 0°C., and −8° C.). Plasminogen activation was relatively high at lowtemperatures (e.g., 0° C. or −8° C.) and was much less at highertemperatures. In other words, these researchers found that, for tPA,cooling to a hypothermic temperature from normal body temperatureincreased fibrinolytic activity.

[0381] As above, it is believed that such trends may be extended topatients without lack of accuracy. In this case, patients may beprovided with tPA and may undergo hypothermia using an above deviceplaced in an artery supplying blood to a thrombosed vessel. The cathetermay include a separate lumen through which tPA may be delivered. Acoolant or working fluid may be supplied to the cooling catheter,causing the catheter and the adjacent blood to cool. This cooling stepmay include the step of inducing turbulence in the blood flowing in thevessel and/or in the working fluid. tPA may be delivered through theseparate drug delivery lumen. In this case, the patient may not berewarmed until the drug delivery is complete, or until the thrombus isdissolved.

EXAMPLE FIVE (TPA)

[0382] Researchers have further investigated the effect of temperatureon the fibrinolytic activity of tPA. Clots were treated with tPA inconcentrations of 0.3 μg/ml, 1.0 μg/ml, and 3.0 μg/ml and incubated atvarious temperatures from 24° C. to 40° C. The amount of clot lysiscorrelated with temperature at all concentrations. However, contrary tothe results indicated in Example Four, the amount of clot lysis at lowertemperatures was less than that at higher temperatures. It isconjectured that heating may have enhanced the activation of plasminogenby the tPA, and that such heating may have a similar effect in patients.This general enhancement has also been seen in UK and SK systems.

[0383] Further research is clearly necessary to determine the optimalprocedure. In any case, an embodiment of the method of the invention maybe employed to advantageously perform either heating or cooling in animproved way. To enhance the activation of plasminogen by tPA, a warmsaline solution may be provided in a catheter of the type describedabove. The warm saline solution transfers heat to the blood at a heattransfer element. An appropriate temperature range for the warm salinesolution at a point within the heat transfer element may be about 38° C.to 74° C.

EXAMPLE SIX (UK)

[0384] Researchers have also investigated the effect of temperature onthe fibrinolytic activity of UK. In one such effort, clots were treatedwith a mixture of UK at temperatures of 4° C. and 28° C. A certainamount of fibrinolytic activity was induced by the introduction of theUK to the clots. Heating to 28° C. caused a second phase of activation,resulting in complete conversion of all plasminogen to plasmin, and thusincreased fibrinolytic activity. In other words, heating from a very lowtemperature (4° C.) to a hypothermic temperature (28° C.) increased clotlysing. As above, it is believed that such trends may be extended topatients. As may be noted, this Example may be analogous to that ofExample Three because of the rewarming step; a similar procedure may beemployed to perform the procedure on patients.

[0385] The above examples indicate how drugs may be combined withtemperature-altering devices as, e.g. are disclosed above, to providesimultaneous cooling and thrombolysis. This combination provides a powerdual therapy which may be advantageously employed to aggressively treatstroke and other similar body insults. When dual therapies are employed,a cooling catheter may be inserted in one femoral artery for transit tothe brain for neural protection. Of course, a heating catheter would beemployed if a temperature rise were desired. Another catheter mayprovide the drug delivery. Alternatively, the heating or coolingcatheter may have disposed therein a lumen for drug delivery. Forexample, the lumen may be coaxial with the catheter and may be disposedalong the centerline of the catheter and heat transfer element.Alternatively, the lumen may be disposed along one portion of the wallof the outlet lumen. The drug delivery lumen may have an outlet at a tipof the heat transfer element. Examples of such catheters are disclosedin U.S. patent application Ser. No. 09/215,040, filed Dec. 16, 1998, andentitled “Method and Device for Applications of Selective OrganCooling”, the entirety of which is incorporated by reference herein.These drug delivery catheters are particularly useful in dispensing thedrug or enzyme regionally, into a blood vessel containing the thrombusor into a blood vessel in fluid communication with the thrombosed bloodvessel.

[0386] The above examples have used known drugs. However, for all of theabove and for similar techniques, an appropriate isoform of an enzymemay be employed to allow enzymatic activity at temperatures other thannormal body temperature. One way to choose appropriate isoforms forthese enzymes is by searching for the same in cold climates. Forexample, SK is a bacterial enzyme. Bacteria live in many differenttemperature environments. It is common to find or select an enzyme for acertain process or temperature by finding bacteria that live inenvironments having the desired temperature.

[0387] As another example, the polymerase chain reaction is apolynucleotide amplification process that requires an enzyme capable ofsurviving high temperatures. These enzymes were located in bacterialiving in hot springs and thermal vents on the sea floor. Therefore, itis likely that certain bacteria that live in room temperatureenvironments or arctic-like environments will have enzymes similar tothose desired, i.e., SK that can survive hypothermic environments.

[0388] tPA and UK, on the other hand, are recombinant forms of humanenzymes. As such, tPA and UK could be genetically altered to maintaintheir activity at lower temperatures. For example, the protein backbonecould be changed to yield higher tPA or UK activity at lowertemperatures.

[0389] Such “temperature-specific” enzymes or drugs may beadvantageously used to localize the effect of the enzymes or drugs. Someenzymes or drugs are considered to have risks associated with their usedue to total body effects. For example, some thrombolytic drugs areprovided only sparingly because of the risk of hemorrhage. This risk ispresent because current drugs are active at a working temperature whichis within the blood temperature range of the vascular system, andbecause the drugs pervade the entire vascular system. The bloodtemperature range of the vascular system is referred to here as beingwithin a first temperature range and as having an average temperature ata first temperature. Drugs provided to lyse thrombi also reduce clottingthroughout the vascular system, increasing the risk of hemorrhage. Ofcourse, such effects are not limited to thrombolytic drugs.

[0390] The invention provides a way to reduce such total body risks. Asdiscussed above, an appropriate isoform of an enzyme may be employed toallow enzymatic activity at temperatures other than within a normal bodytemperature range, e.g., the first temperature range described above. Inother words, for cooling, an enzyme may be found with a workingtemperature range at a hypothermic temperature. Such an enzyme may notwork within the above-described first temperature range. For example, athrombolytic isoform may lyse clots where the blood temperature ishypothermic but may not produce fibrinolytic effects where the bloodtemperature is not hypothermic.

[0391] This type of drug or enzyme may be advantageously used in thepresent invention. For example, a heat transfer element may be placed inthe vasculature upstream of a vicinity in which a clot has formed. Theheat transfer element may be used to cool the blood flowing to thevicinity so that the blood in the vicinity achieves a hypothermictemperature. An isoform of a thrombolytic drug may be delivered to thevicinity, the isoform having a working temperature at the hypothermictemperature. The isoform of the thrombolytic drug may then act to lysethe clot. The thrombolytic drug does not produce fibrinolytic activityin portions of the vasculature that are not at the hypothermictemperature, i.e., the rest of the body. An advantage to this method isthat even very strong thrombolytics may be used to effectively lyseclots, with significantly less concern about the above-describedfibrinolytic side effects throughout the remainder of the body.

[0392] While the method of the invention has been described with respectto specific devices and techniques which may be used to cool blood,other techniques or devices may also be employed. The embodiments of themethod of the invention may advantageously employ the turbulenceinducing devices and techniques disclosed above to enhance the heattransfer and thus the heating or cooling of the blood.

[0393] Furthermore, the invention has been described predominantly withrespect to a particular lysing system: the lysing of a blood clot in ablood vessel such as is caused by stroke or myocardial infarction.However, the methods of the invention can be equally applied to alteringthe activity of any enzyme relative to its activity at normaltemperatures. Furthermore, the invention may be applied to coolingsolids, such as volumes of tissue, rather than blood flows or staticvolumes of blood. Moreover, the invention can be applied to heatingblood or tissue, especially when such heating advantageously enhancesdesired activity in a specific enzyme.

[0394] The invention has also been described with respect to certaindrug therapies. It will be clear to one of skill in the art that variousother drugs may be employed in the method of the invention, so long asthey have characteristics similar to those described above.

[0395] Additional Therapies

[0396] Turning now from thermoregulatory drugs to additional therapies,the method and device according to the embodiments of the invention mayalso play a significant role in treating a variety of maladies involvingcell damage. Optimal rewarming strategies for these indications aredescribed later.

[0397] Stroke

[0398] A patent application incorporated by reference above disclosesdevices and methods for enhancing fibrinolysis of a clot by coolingblood flowing in an artery. The present invention may also use bloodcooling to substantially reduce platelet aggregation as there is asignificant reduction in platelet activity at reduced temperatures. Suchreduction may take place by inhibiting enzyme function, although theactual methodology is unclear. This reduction in platelet aggregation,as well as the enhanced fibrinolysis noted above, may reduce oreliminate current dependence on such drugs as tPA or Rheopro.

[0399] Myocardial Infarction

[0400] The above-described venous cooling may also provide a number ofbenefits for patients undergoing myocardial infarction.

[0401] Current therapies for treating myocardial infarction involvethree areas. Thrombolysis or stenting are used to establish reflow. Theoxygen supply is increased by directly supplying the patient with oxygenand by vasodilation with nitrates. And the oxygen demand is lessened bydecreasing the heart rate and the blood pressure.

[0402] Devices and methods according to the present invention can workwell in combination with these current therapies. For example, thedevice and method may lessen the heart's demand for oxygen by providingcooled blood to the heart. The cooled blood in turn cools the innerchambers of the heart, essentially from the inside. Hearts undergoingmyocardial infarction may beat very fast due to an agitated state of thevictim. However, cooled blood may induce a state of bradycardia thatreduces the demand for oxygen by the heart per se.

[0403] To establish reflow and the oxygen supply, the enhancedfibrinolysis, discussed above, may also dissolve the clot, allowing moreblood flow and more oxygen delivered to the heart. As mentioned above,platelet aggregation may be reduced. Additionally, conduction throughthe subendocardium, cooling the heart, may reduce the overall metabolicactivity of the heart as well as protect the subendocardium from celldamage.

[0404] It is additionally noted that reflow is often accompanied byreperfusion injury which can further damage cells. Neutrophil activationoccurs as part of reperfusion injury. Hypothermia can limit suchactivation and thus can limit reperfusion injury.

[0405] Thus, numerous therapies may be delivered by one device.Therefore, e.g., currently-employed “beta-blocker” drugs used to reduceheart rate in patients undergoing infarcts may not need to be employedin patients undergoing these hypothermic therapies.

[0406] Re-Stenosis

[0407] Another application of the device and method may be in thetreatment of stenotic arteries. Stenotic arteries are vessels that havenarrowed due to a build-up of tissue and/or plaque atheroma. Stenoticvessels are treated by angioplasty or stenting, which opens the artery.During treatment the vessel wall may be injured. Such injuries often(20-50%) cause an inflammatory reaction that eventually causes thevessel to undergo re-stenosis after a period of time, which may rangefrom 6-12 months or even several years later.

[0408] Hypothermia is known to mitigate inflammatory responses. Forexample, one of the initial steps in the process of re-stenosis is themigration of macrophages or white blood cells to the injured area.Hypothermia can limit this migration. Hypothermia can also inhibitreactions and processes initiated by molecules acting in an autocrine orparacrine fashion. Hypothermia may also limit the release of severalgrowth factors (at the site of injury) such as PDGF and EGF that act inthese fashions.

[0409] CV Rewarming/Surgery

[0410] According to one aspect of the present invention, a procedure isprovided by which a surgeon is able to perform a coronary bypassprocedure with hypothermic protection, while at the same time avoidingmany of the disadvantages associated with the use of traditionalexternal cardiopulmonary bypass systems and aortic clamping procedures.

[0411] In one embodiment of the present invention, a heat transferelement is provided within a blood vessel of the body such that blood iscooled in vivo upon contact with the heat transfer element.

[0412] The heat transfer element can be provided in either arterial orvenous blood vessels. One preferred location for the heat transferelement is the inferior vena cava, which typically ranges from 15 mm to25 mm in diameter. A preferred method by which the heat transfer elementis provided at this position is via entry at the femoral vein.

[0413]FIG. 55 is a schematic representation of the use of a heattransfer element in cooling the body of a patient. The apparatus shownin FIG. 55 includes a working fluid supply 476, preferably supplying achilled aqueous solution, a supply catheter 478 and a heat transferelement 102. The supply catheter 478 may have a substantially coaxialconstruction. An inner coaxial lumen within the supply catheter 478receives coolant from the working fluid supply 476. The coolant travelsthe length of the supply catheter 478 to the heat transfer element 102that serves as the cooling tip of the catheter. At the distal end of theheat transfer element 102, the coolant exits an insulated interior lumenand traverses the length of the heat transfer element 102 in order todecrease the temperature of the surface of the heat transfer element102. The coolant then traverses an outer lumen of the supply catheter478 so that it may be disposed of or recirculated. The supply catheter478 is a flexible catheter having a diameter sufficiently small to allowits distal end to be inserted percutaneously into an accessible bloodvessel, shown in FIG. 55 as the right femoral vein. The supply catheter478 is sufficiently long to allow the heat transfer element 102 at thedistal end of the supply catheter 478 to be passed through the vascularsystem of the patient and placed in the blood vessel of interest, herethe inferior vena cava. The method of inserting the catheter into thepatient and routing the heat transfer element 102 into a selected arteryor vein is well known in the art.

[0414] In the embodiment of FIG. 55, the narrowest blood vesselencountered by the heat transfer element as it travels to the inferiorvena cava is the femoral artery, which generally ranges from 5 to 8 mmin diameter. Accordingly, in this embodiment of the invention, thediameter of the heat transfer element is about 4 to 5 mm in diameter.

[0415] In order to obtain the benefits associated with hypothermiaduring a coronary bypass procedure, it is desirable to reduce thetemperature of the blood flowing within the body to less than 35° C.,more preferably between 30 and 35° C., and most preferably 32±2° C.Given a typical blood flow rate of approximately 2.5 to 4l/min, moretypically about 3.5l/min, in the inferior vena cava, the heat transferelement preferably absorbs 200 to 300 Watts of heat when placed in thisvein, in order to induce the desired cooling effect. Approximate coolingtime is 15 to 30 minutes.

[0416] Cooling the body to less than 35° C. provides a number ofdesirable effects. First, cooling will induce a bradycardia of theheart. Reduced heart rates corresponding to about ⅔ of the normal heartrate are common at the preferred temperature of 32±2° C. By slowing thebeating of the heart, the present invention facilitates surgery duringbeating heart procedures. Such procedures are well known in the art. Forexample, the performance of coronary surgery on the beating heart isdescribed by Benetti et al in “Coronary Revascularization With ArterialConduits Via a Small Thoracotomy and Assisted by Thoracoscopy, AlthoughWithout Cardiopulmonary Bypass”, Cor. Europatum, 4(1): 22-24 (1995), andby Westaby, “Coronary Surgery Without Cardiopulmonary Bypass” in theMarch, 1995 issue of the British Heart Journal. Additional discussion ofthis subject matter can be found in Benetti et al, “Direct myocardialrevascularization without extracorporeal circulation. Experience in 700patients”, Chest, 100(2): 312-16 (1991), Pfister et al, “Coronary arterybypass without cardiopulmonary bypass” Ann. Thorac. Surg., 54:1085-92(1992), and Fanning et al, “Reoperative coronary artery bypass graftingwithout cardiopulmonary bypass”, Ann. Thorac. Surg., 55:486-89 (1993).Each of the above articles is hereby incorporated by reference.

[0417] Moreover, the general anesthesia associated with coronary bypasstechniques is often accompanied by vasodilation in the patient, whichdecreases organ perfusion and hence increases the risk of ischemia. Thiseffect, however, is combated by the hypothermia induced in accordancewith the present invention, which promotes vasoconstriction.

[0418] Cooling the body also protects the organs from ischemic damagedue to low circulatory flow rates or due to emboli formation. Forexample, as previously noted, procedures are known in the art in which(1) the heart is intermittently stopped and restarted or (2) the heartis stopped and a small intracorporeal pump is used to providecirculatory support. These techniques and others like them allow thesurgeon to operate on a still or nearly still heart. However, each ofthese techniques also places the patient at risk from ischemia. Bylowering the body temperature of the patient to a preferred temperatureof 32±2° C. in accordance with the present invention, however, theoxygen demand of the bodily tissue, and hence the danger of ischemiaassociated with these procedures, is reduced.

[0419] More specifically, with some techniques in which alternatingperiods of heartbeat and heart arrest are provided, the heart is stoppedor nearly stopped using drugs such as beta-blockers, and a pacing deviceis used to cause the heart to beat on demand. An example of one suchsystem is the TRANSARREST system; Corvascular, Inc., Palo Alto, Calif.In other techniques, the heart is momentarily stopped or slowed byelectrically stimulating the vagus nerve. See, e.g., U.S. Pat. Nos.5,913,876 and 6,006,134, the disclosures of which are herebyincorporated by reference. (As noted in U.S. Pat. No. 5,913,876, one ormore heart pacing devices, such as a Pace port-Swann pulmonary arterycatheter, may be inserted in conventional fashion to the patient's heartand used to restore the beating of the heart during the surgery, in theevent the heart is slow to revive after a nerve stimulating signal isturned off.) Each of these techniques is associated with a circulatoryflow rate that can be significantly lower than normal cardiac output.

[0420] The risks of ischemia due to low circulatory flow rates, however,are reduced in accordance with an embodiment of the invention. Inparticular, before manipulating the heartbeat of the patient, a heattransfer element is inserted into the vasculature of the patient and thebody temperature of the patient is reduced, preferably to 32±2° C. Asnoted above, by lowering the body temperature, the body's oxygen demandis reduced, decreasing the risk of ischemia. Moreover, a reduction inbody temperature in accordance with the present invention is accompaniedby vasoconstriction, which decreases the circulatory flow rate that isrequired for adequate organ perfusion and consequently further decreasesthe risk of ischemia.

[0421] The present invention is also useful in connection withtechniques in which the heart is stopped or nearly stopped and anintracorporeal pump is used to support circulation. For example,techniques are known in which circulatory support is provided duringcoronary bypass by a pump positioned in the patient's aortic valve. See,for example, M. S. Sweeney, “The Hemopump in 1997: A Clinical,Political, and Marketing Evolution”, Ann. Thorac. Surg., 1999, Vol. 68,pp. 761-3, the entire disclosure of which is hereby incorporated byreference. In this reference, a coronary bypass operation is describedin which esmolol, a short acting beta-blocker, is administered to calmthe heart during surgery. A Medtronic Hemopump® is used for circulatorysupport and the patient's own lungs are used for oxygenation. At thecore of the Hemopump is a small, rapidly turning Archimedes screw. Thepump assembly is made of stainless steel and is attached to a siliconerubber inlet cannula. The cannula is positioned across the aortic valveand into the left ventricle. The pump assembly is catheter mounted tofacilitate placement of the pump in its operating position. For example,the pump assembly is ordinarily inserted into the femoral artery of thethigh, whereupon it is guided to the left ventricle. Once in place, thecannula acts to entrain blood and feeds it to the pump portion, whichthen pumps the blood into circulation via the aorta. The pump isoperated by the creation of pulsing electromagnetic fields, which causerotation of a permanent magnet, resulting in operation of the Archimedesscrew. Electrical power is provided from a console outside the patient.The pumping action is axial and continuous (i.e., non-pulsatile). Due tothe design of the Hemopump, rotational speeds on the order of 10,000 to20,000 rpm can be used to produce blood flow of about four liters perminute or less (depending on the model) without significant hemolysis.Additional details are found in M. C. Sweeney and O. H. Frazier,“Device-supported myocardial revascularization; safe help for sickhearts”, Ann. Thorac. Surg. 1992, 54: 1065-70 and U.S. Pat. No.4,625,712, the entire disclosures of which are hereby incorporated byreference.

[0422] This technique and others like it, however, are frequentlyassociated with circulatory flow rates (i.e., about 4 l/min or less)that are lower than normal cardiac output (i.e., about 5 l/min for manypeople) placing the patient at ischemic risk. By lowering the bodytemperature of the patient to a preferred range of 32±2° C. inaccordance with the present invention, however, the blood vessels areconstricted and oxygen demand of the bodily tissue is reduced,increasing organ perfusion and reducing the danger of ischemia for agiven circulatory output.

[0423] As noted above, in a preferred embodiment of this first aspect ofthe invention, the heat transfer element is provided in the inferiorvena cava, which is accessed via the femoral vein. In contrast, theHemopump is preferably provided in the left ventricle, which is accessedvia the femoral artery. In this way, both the heating element and theHemopump can be concurrently placed in the body in a minimally invasivefashion.

[0424] According to another aspect of the invention, a hypothermicmedical procedure is performed on a patient in a conscious orsemiconscious state. An example of a situation where such a hypothermicmedical procedure may be performed is one in which a patient hassuffered a stroke and hypothermia is induced in the brain to reduceischemic damage.

[0425] Such procedures can be performed either to cool the entire bodyof the patient or a region within the patient's body, typically anorgan.

[0426] The entire body can be cooled using the procedures discussedabove. For example, the heat transfer element is preferably provided ina venous blood vessel, more preferably the inferior vena cava, to effectcooling of the entire body.

[0427] In order to intravascularly regulate the temperature of aselected region, the heat transfer element may be placed in a feedingartery of the region to absorb or deliver the heat from or to the bloodflowing into the region. The heat transfer element should be smallenough to fit within the feeding artery while still allowing asufficient blood flow to reach the region in order to avoid ischemicdamage. By placing the heat transfer element within the feeding arteryof a region, the temperature of the region can be controlled, whilehaving less effect on the remaining parts of the body. Using the brainas an example, the common carotid artery supplies blood to the head andbrain. The internal carotid artery branches off of the common carotid todirectly supply blood to the brain. To selectively cool the brain, theheat transfer element is placed into the common carotid artery, or boththe common carotid artery and the internal carotid artery. The internaldiameter of the common carotid artery ranges from 6 to 8 mm and thelength ranges from 80 to 120 mm. Thus, the heat transfer elementresiding in one of these arteries cannot be much larger than 4 mm indiameter in order to avoid occluding the vessel, which would result, forexample, in ischemic damage.

[0428] When hypothermia is induced in a patient, less than desirableside effects can occur in the patient. For example, hypothermia is knownto activate the sympathetic nervous system in a conscious orsemiconscious patient, resulting in a significant norepinephrineresponse. Norepinephrine, in turn, binds to beta sites including thosein the heart, causing the heart to beat harder and more rapidly,frequently resulting in cardiac arrhythmia and increased risk ofmyocardial ischemia. In accordance with an embodiment of the presentinvention, however, a beta-blocker is administered to the patient.Without wishing to be bound by theory, it is believed that thebeta-blocker offsets the norepinephrine binding noted above. In general,the beta-blocker may be administered before the patient coolingcommences, and preferably immediately before patient cooling commences.

[0429] Preferred beta-blockers for this aspect of the invention includeβ1 blockers, β1β2 blockers and αβ1β2 blockers. Preferred β1 blockersinclude acebutolol, atenolol, betaxolol, bisoprolol, esmolol andmetoprolol. Preferred β1β2 blockers include carteolol, nadolol,penbutolol, pindolol, propranolol, sotalol and timolol. Preferred αβ1β2blockers include carvedilol and labetalol.

[0430] The heightened demand that hypothermia places on the heart ofconscious or semiconscious patents may also be relieved, for example,with heating blankets. However, vasoconstriction limits the heatingability of the heating blankets. Without wishing to be bound by theory,it is believed that the above-noted production of norepinephrineactivates alpha-receptors, for example, in the peripheral blood vessels,causing this vasoconstriction. The vasoconstriction can be offset, inaccordance with the present invention, by treating the patient withalpha-blockers when indicated, preferably before cooling is initiated.Preferred alpha-blockers include labetalol and carvedilol.

[0431] In the various embodiments of the invention, once the medicalprocedure is completed, the heat transfer element is preferably used towarm the body back to its normal temperature, i.e., 37° C.

[0432] According to another aspect of the present invention, a procedureis provided in which hypothermia is induced in a human patient in needof neural protection due to ischemic neural conditions by positioning aheat transfer element in a blood vessel of the patient. To enhance theneural protection provided by the induced hypothermia, an effectiveamount of one or more therapeutic agents is administered to the patient,which therapeutic agents may include (a) an antipyretic agent, (b) afree-radical scavenger, and/or (c) an N-methyl-D-aspartame receptorantagonist.

[0433] Preferred antipyretic agents for the purposes of the presentinvention are antipyretic agents having anti-inflammatory properties aswell as antipyretic properties, such as dipyrone. Dipyrone has beenwithdrawn or removed for the market in the U.S., but it is availablefrom Hoechst AG. Determining the dosage forms, dosage amounts and dosagefrequencies that are effective to supplement the neural protectionprovided by hypothermia is well within the abilities of those ofordinary skill in the art. In the event that the ischemic neuralconditions are associated with fever, such as that commonly associatedwith stroke, the antipyretic agent is administered until the risk offever subsides, typically at least three days after hypothermia issuspended.

[0434] Preferred free radical scavengers for the purposes of the presentinvention include tirilazad or any pharmaceutically active saltsthereof. Tirilazad mesylate, which is both a free-radical scavenger anda lipid peroxidation inhibitor, is manufactured by Upjohn under thetrade name FREEDOX and is indicated to improve survival and functionaloutcome in male patients with aneurismal subarachnoid hemorrhage.Determining those dosage forms, dosage amounts and dosage frequenciesthat are effective to supplement the neural protection provided byhypothermia is well within the abilities of those of ordinary skill inthe art.

[0435] Preferred N-methyl-D-aspartame receptor antagonists for thepractice of the present invention include dextromethorphan, MgCl₂ andmemantine, more preferably dextromethorphan and pharmaceutically activesalts of the same. Dextromethorphan is commonly found in syrup form andis available from a variety of sources. A preferred dosage fordextromethorphan is 10 to 30 mg orally every four to eight hours for atleast three days. Determination of other appropriate dosage forms,dosage amounts and dosage frequencies that are effective to supplementthe neural protection provided by hypothermia is well within theabilities of those of ordinary skill in the art.

[0436] Combinations of the above therapeutic agents are also possible.For example, in one preferred embodiment, a free radical scavenger andan N-methyl-D-aspartame receptor antagonist are co-administered alongwith the hypothermia.

[0437] The method of the present invention is appropriate for varioustypes of ischemic neural conditions, including ischemia of the spinalcord, cerebral ischemia including stroke, and so forth.

[0438] The need for neural protection due to ischemic neural conditionscan occur in various contexts. In some instances, a patient hasexperienced an unanticipated ischemic injury, for example, due tophysical trauma, such as that associated with an automobile accident, ordue to a pathological event, such as a stroke. Under such circumstances,it is preferred that hypothermia be induced and therapeutic agent beapplied within 6 to 12 hours after the patient has experienced theischemic injury.

[0439] In other instances, the patient is at risk of ischemic neuralconditions due to a medical procedure such as cardiac surgery, brainsurgery including aneurysm surgery, and so forth. In these instances, itis preferred that hypothermia be induced and that the therapeutic agentbe administered before to the medical procedure commences.

[0440] In addition, in some applications, it may be advantageous toattach a stent to the distal end of the heat transfer element. The stentmay be used to open arteries partially obstructed by atheromatousdisease prior to initiation of heat transfer. Further, the device may beused to deliver drugs such as blood clot dissolving compounds (e.g.,tissue plasminogen activator (“tPA”), urokinase, prourokinase,streptokinase, etc.) or neuroprotective agents (e.g., selectiveneurotransmitter inhibitors). In addition to therapeutic uses, thedevice may be used to destroy tissue such as through cryosurgery.

[0441] Fever

[0442] A one or two-step process and a one or two-piece device may beemployed to intravascularly lower the temperature of a body in order totreat fever. A cooling element may be placed in a high-flow vein such asthe vena cavae to absorb heat from the blood flowing into the heart.This transfer of heat causes a cooling of the blood flowing through theheart and thus throughout the vasculature. Such a method and device maytherapeutically be used to treat fever.

[0443] A heat transfer element that systemically cools blood should becapable of providing the necessary heat transfer rate to produce thedesired cooling effect throughout the vasculature. This may be up to orgreater than 300 watts, and is at least partially dependent on the massof the patient and the rate of blood flow. Surface features may beemployed on the heat transfer element to enhance the heat transfer rate.The surface features and other components of the heat transfer elementare described in more detail below.

[0444] One problem with treating fever with cooling is that the cause ofthe patient's fever attempts to defeat the cooling. Thus, a high powerdevice is often required.

[0445] Of course, the use of the superior vena cava is only exemplary.It is envisioned that the following veins may be appropriate topercutaneously insert the heat transfer element: femoral, internaljugular, subclavian, and other veins of similar size and position. It isalso envisioned that the following veins may be appropriate in which todispose the heat transfer element during use: inferior vena cava,superior vena cava, femoral, internal jugular, and other veins ofsimilar size and position. Arteries may also be employed if a fevertherapy selective to a particular organ or region of the body isdesired.

[0446] In a method according to an embodiment of the invention fortreating patients with fever, the heat transfer element as described maybe placed in any of several veins, including the femoral, the IVC, theSVC, the subclavian, the braichiocephalic, the jugular, and other suchveins. The heat transfer element may also be placed in appropriatearteries for more selective fever reduction.

[0447] The amount of cooling performed may be judged to a firstapproximation by the rate of cool-down. The amount of cooling isproportional to the difference between the temperature of the blood andthe temperature of the heat transfer element or cooling element. Thus,if the temperature of the blood is 40° C. and the temperature of thecooling element is 5° C., the power extracted will be greater than ifthe temperature of the blood is 38° C. and the temperature of thecooling element is maintained at 5° C. Thus, the cool-down or coolingrate is generally greatest at the beginning of a cooling procedure. Oncethe patient temperature begins to approach the target temperature,usually normothermia or 37° C., the cooling rate may be reduced becausethe temperature differential is no longer as great.

[0448] In any case, once the patient reaches the normothermictemperature, it is no longer easy to guess whether, in the absence ofthe cooling therapy, the patient would otherwise be feverish or whetherthe fever has abated. One embodiment of the invention allows adetermination of this.

[0449] First, it is noted that the power extracted can be calculatedfrom the temperature differential between the working fluid supplytemperature and the working fluid return temperature. In particular:

[0450] P_(catheter)=M c_(f) ΔT_(f)

[0451] Where P_(catheter) is the power extracted, M is the mass flowrate of the working fluid, c_(f) is the heat capacity of the workingfluid, and ΔT is the temperature differential between the working fluidas it enters the catheter and as it exits the catheter. Accordingly,P_(catheter) can be readily calculated by measuring the mass flow of thecirculating fluid and the temperature difference between the workingfluid as it enters and exits the catheter. The power removed by thecatheter as determined above may be equated to a close approximation tothe power that is lost by the patient's body.

[0452] In general, a closed-form solution for the power P required tocool (or heat) a body at temperature T to temperature T₀ is not known.One possible approximation may be to assume an exponential relationship:

P=α(exp β(T−T _(o))−1)

[0453] Taking the derivative of each side with respect to temperature:$\frac{\partial P}{\partial T} = {{\alpha\beta}\quad ^{\beta {({T - T_{0}})}}}$

[0454] and taking the inverse of each side:$\frac{\partial T}{\partial P} = {{\frac{1}{{\alpha\beta}\quad ^{\beta {({T - T_{0}})}}}\quad {or}\quad \Delta \quad T} \approx {\frac{\partial T}{\partial P}\Delta \quad P}}$

[0455] where ΔT is the temperature differential from nominal temperatureand ΔP is the measured power. A close approximation may be obtained byassuming the relationship is linear. Equivalently, a power seriesexpansion may be taken, and the linear term retained. In any case,integrating, assuming a linear relationship, and rearranging:

P=α(T−T ₀)

[0456] where the constant of proportionality has units of watts/degreeCelsius. One can determine the constant of proportionality a using twopoints during the therapy when both T and P are finite and known. Onemay be when therapy begins, i.e., when the patient has temperature T andthe catheter is drawing power P. Another point may be obtained when T=T₀and P=P₀. Then, for any P, T is given by:$T_{{absence}\quad {of}\quad {therapy}} = {T_{0} + \frac{P_{{atT}_{0}}}{\alpha}}$

[0457] An example of this may be seen in FIG. 56, which shows aflowchart of an embodiment of a method of the invention. Referring tothe figure, a patient presents at a hospital or clinic with a fever(step 480). Generally, such a patient will have a fever as a result of amalady or other illness for which hospitalization is required. Forexample, the majority of patients in ICUs present with a fever.

[0458] A catheter with a heat transfer element thereon may be inserted(step 482). The initial power withdrawn P_(start) and body temperatureT_(start) may be measured (step 484), and the therapy begun (step 486).The therapy continues (step 488), and P and T are periodically,continuously, or otherwise measured (step 490). The measured T iscompared to the normothermic T=T₀, which is usually about 37° C. (step492). If T is greater than T₀, the therapy continues (step 488). If T isless than T₀, then the power P₀ is measured at T=T₀ (step 494). By theequations above, a constant of proportionality α may be uniquelydetermined (step 496) by knowledge of T_(start), P_(start), P₀, and T₀.From α, T_(start), P_(start), P₀, and T₀, T_(absence of cooling) may bedetermined (step 498). T_(absence of cooling) is then compared to T₀(step 500). If T_(absence of cooling)>T₀, then the patient is stillgenerating enough power via their metabolism to cause a fever if thetherapy were discontinued. Thus, therapy is continued (step 502). IfT_(absence of cooling)<=T₀, then the patient is no longer generatingenough power via their metabolism to cause a fever if the therapy werediscontinued. Thus, therapy is discontinued (step 504). Variations ofthe above method will be apparent to those of ordinary skill in the art.

[0459] The manifold of the present invention is generally shown at 506in FIG. 57. The manifold 506 is connected at its distal end 508 to athree lumen catheter 104 that circulates fluid for any of a variety ofmedical and therapeutic purposes. However, for purposes of discussiononly, the present invention will be described in terms of a heattransfer catheter in which fluid is circulated through the catheter tocool or heat the whole body or a selected portion of a patient. A strainrelief sleeve 514 protects the catheter 512 from kinking immediatelyadjacent to the distal end 508 of the manifold 506.

[0460] The three lumen catheter 512, as shown in FIG. 58, has an outertube 530, an intermediate tube 538 and an inner tube 534. The catheterhas a guide wire space or lumen 540 defined by the inner surface ofinner tube 534. An outer annular lumen 542 is defined between the innersurface of outer tube 530 and the outer surface of intermediate lumen538. An inner annular lumen 536 is defined between the inner surface ofintermediate tube 538 and the outer surface of the inner tube 534.

[0461] In operation, once the catheter 512 is in place, a working fluidsuch as saline or other aqueous solution may be circulated through thecatheter 512. Fluid flows up the inner annular lumen 536. At the distalend of the catheter 512, the working fluid exits the inner annular lumen536 and enters outer annular lumen 542. If the catheter 512 is employedto transfer heat, it may be constructed from a highly conductivematerial so that the temperature of its external surface may reach veryclose to the temperature of the working fluid. In order to avoid theloss of thermal energy from the working fluid within the inner annularlumen 536, an insulating coaxial layer may be provided within thecooling catheter 512. In some cases a substantial portion of the entirelength of the outer annular lumen 542 may be insulated except at one ormore particular locations through which heat is to be directly appliedto the portion of the body in contact therewith. Referring again to FIG.57, the manifold 506 includes a first manifold 518, which providesaccess to the inner annular lumen 536 via port 524. The manifold 506also includes a second manifold 516, which provides access to the outerannular lumen 542 via port 522. The first manifold 518 also includes aguide wire entry port 526, which provides access to the guide wire lumen540 for a guide wire (not shown). When installed, the guide wiregenerally follows the central axis 521 through the manifold. As shown,guide wire entry port 526 may be tapered so that the guidewire can beeasily inserted without damage. The first manifold 518 has a proximalend 510 on which a Luer fitting 520 is located.

[0462] Console

[0463] With reference to FIG. 59, an embodiment of a heat transfercatheter system 544 includes a heat transfer catheter 546, a controlsystem 548, and a circulation set 550 housed by the control unit system548. The control system 548 may be equipped with an output display 552and input keys 554 to facilitate user interaction with the controlsystem 548. A hood 556 is pivotally connected to a control unit housing558 for covering much of the circulation set 550.

[0464] With reference additionally to FIGS. 60 and 61, in a preferredembodiment, the catheter 568 is a heat transfer catheter such as, butnot by way of limitation, a hypothermia catheter capable ofintravascular regulation of the temperature of a patient's body or oneor more selected organs. The catheter 568 may include a heat transferelement 562 located at a distal portion thereof. In the embodiment ofthe heat transfer element shown, the heat transfer element 562 includesa supply lumen 564 and a return lumen 566. The supply lumen 564 andreturn lumen 566 preferably terminate at respective distal points in adistal portion of the heat transfer element 562 and terminate atrespective proximal points at a supply lumen port 570 and a return lumenport 572 in catheter handle 573.

[0465] The heat transfer element 562 may be placed in the vasculature ofthe patient to absorb heat from or deliver heat to surrounding bloodflowing along the heat transfer element 562, thereby regulating thetemperature of a patient's body or one or more selected organs. In ananalogous fashion, the heat transfer element 562 may be used within avolume of tissue to regulate the tissue temperature by absorbing heatfrom or delivering heat to a selected volume of tissue. In the lattercase, heat transfer is predominantly by conduction.

[0466] In an exemplary application, the heat transfer catheter 568 maybe used to cool the brain. One or more other organs, as well as thewhole body, may also be cooled and/or heated, i.e., temperaturecontrolled. The common carotid artery supplies blood to the head andbrain. The internal carotid artery branches off the common carotidartery to supply blood to the anterior cerebrum. The heat transferelement 562 may be placed into the common carotid artery or into boththe common carotid artery and the internal carotid artery via thefemoral artery or other well known vascular routes. Heat transfer fluidsupplied, chilled, and circulated by the circulation set 550 causes theheat transfer element 562 to draw heat from the surrounding blood flowin the carotid artery or internal carotid artery, causing cooling of thebrain to, for example, reduce the effects of certain body injuries tothe brain.

[0467] Although the catheter 568 has been described as including aspecific heat transfer element 562, it will be readily apparent to thoseskilled in the art that the circulation set of the present invention maybe used with heat transfer catheters including heat transfer elementsother than the specific heat transfer element 562 described above.Further, although the circulation set 550 is described in conjunctionwith a heat transfer catheter, it will be readily apparent to thoseskilled in the art that the circulation set of the present invention maybe used in conjunction with catheters other than hypothermia or heattransfer catheters. For example, the circulation set may be used withcatheters that require a fluid to be supplied to and/or circulatedthrough the catheter.

[0468] Circulation Set

[0469] With reference to FIGS. 59 and 62, an embodiment of thecirculation set 550 will now be described. The circulation set 28 550include one or more of the following: a fluid reservoir 574, a pump 576,a filter 578, a heat exchanger 580, a temperature and pressure sensorassembly 584, a supply line 586, and a return line 588. The supply lumenport 570 and return lumen portion are coupled with respective supplylines 586 and return lines 588 of the circulation set 550. The supplyline 586 and return line 588 are preferably comprised of one or morepieces of tubing, connectors, etc. for joining the aforementionedcomponents of the circulation set 550 to the supply lumen port 570 andreturn lumen port 572. The circulation set 550 may supply, filter,circulate, and/or be used to monitor the temperature and pressure of theheat transfer fluid for the catheter 546. Each of these components willnow be described in turn.

[0470] Fluid Reservoir

[0471] In a preferred embodiment, the fluid reservoir 60 is a modified250 ml IV bag made of PVC. The fluid reservoir 574 may be filled with aworking fluid such as, but not by way of limitation, saline, freon, orperfluorocarbon. In order to prevent the working fluid from causing EMIinterference with other electronic devices used in the operating room,the working fluid may be a non-ionic fluid such as, but not by way oflimitation, D5W, D5W with 1.5% glycerine, Sorbitol-Mannitol, andRinger's Solution.

[0472] The fluid reservoir 574 may be used to prime the lines 586, 588and lumens 564, 566 of the system 544. The fluid reservoir 574 includesa supply or inlet tube 590 that communicates at an inlet 592 with thereturn line 588 and communicates at an opposite end or outlet 594 withan inside 596 of the reservoir 574. The fluid reservoir 574 alsoincludes a return or outlet tube 598 that communicates at one end withthe supply line 586 and communicates at an opposite end or inlet 602,with the inside 596 of the reservoir 574.

[0473] The fluid reservoir 574 preferably also includes a mechanism 604for purging, venting or removing air from the system 544. The airpurging mechanism is used to remove air from the lines 586, 588 andlumens after a single use. The pump 576 is used to draw the heattransfer fluid from the fluid reservoir and circulate the fluidthroughout the lines 586, 588 and lumens 564, 566. In an alternativeembodiment, the pump may be a permanent, non-disposable pump.

[0474] Filter

[0475] The filter 578 is preferably a 5 micron filter carried by maleand female housing members. The filter 578 removes impurities from thecirculating heat transfer fluid. In other embodiments of the circulationset 550, the circulation set 550 may include more than one filter 578,the circulation set 550 may include no filters 578, or the filter 578may be a part of one or more components of the circulation set 550.

[0476] Heat Exchanger

[0477] In the embodiment of the circulation set illustrated in FIGS. 59and 62, the heat exchanger 580 is a stainless steel tubing 582 that sitsin a bath 560 of a second heat transfer fluid made of a biocompatiblefluid such as, but not limited to, galden or ethylene glycol. This is anexample of a wet heat exchanger because the tubing 582 resides within aliquid heat transfer fluid. A second heat exchanger (not shown) locatedin the control unit housing 558 regulates the temperature of the bath560 564, 566 of the system 544 and, in a preferred embodiment, includesa needleless polycarbonate valve 606 with a polycarbonate vented spike608. The removal or purging of air from the system 544 is important formaximizing the pressure in the system 544, maximizing heat transfer atthe heat transfer element 562, and preventing air from possibly enteringthe blood stream of the patient caused by a break or leak in thecatheter 568. The outlet 594 of the supply tube 590 may be locatedcloser to the air purging mechanism 604 than the inlet 602 of the returntube 598 or adjacent to the air purging mechanism 604 to inhibit airbubbles supplied by the supply tube 590 from directly entering thereturn tube 598 without the opportunity to be removed by the air purgingmechanism 604. The purging cycle will be discussed in greater detailbelow.

[0478] In an alternative embodiment of the circulation set, the fluidreservoir 574 may supply or prime the system 544 without recirculationof working fluid therethrough. In this embodiment, the reservoir 574 maynot include the supply tube 590 and the air removal mechanism 604. Theair removal mechanism 604 may be located in the circulation set 550outside of the fluid reservoir 574.

[0479] The pump 576 is may be a disposable, plastic micro-pump that isdisposed of or discarded with the other disposable components of thecirculation set 550 for controlling the temperature of the heat transferfluid in the system 544. The heat exchanger 580 is a reusable,non-disposable, wet heat exchanger.

[0480] With reference to FIGS. 63-66, an embodiment of a dry heatexchanger 610 including a disposable, single-use heat exchanger member612 may be used in the circulation set 550. The heat exchanger member612 is removably securable within heat exchanger mold members 614, 616.

[0481] The heat exchanger mold members 614, 616 are preferablyconstructed of a thermoplastic insulative material and may includematching, mirrored serpentine grooves 618 therein. The serpentinegrooves 618 terminate at one end in an inlet groove 620 and terminate atan opposite end in an outlet groove 622. The inlet groove 620 and outletgroove 622 accommodate inlet tube 626 and outlet tube 628 of thedisposable heat exchanger member 612 and corresponding connection tubes(not shown) for connecting to the supply line 586. In an alternativeembodiment, each heat exchanger mold member 614, 616 may have more thanone inlet and/or outlet. Instead of serpentine grooves 618, each heatexchanger mold member may include one or more cavities that formreservoirs that heat transfer fluid flows through. First and second heatexchanger surfaces 624, 632 are located on inner faces of the moldmembers 614, 616. In a preferred embodiment, the heat exchanger surfaces624, 632 are stamped stainless steel pieces of sheet metal that arebonded to the inner faces of the mold members 614, 616 so as to formheat transfer paths 634 (FIG. 64) therebetween. The heat exchangersurfaces 624, 632 preferably have serpentine grooves 636 stampedtherein. In an alternative embodiment of the invention, each groove 636may have a shape that is other than serpentine or there may be more orless channels in each serpentine groove 636. The heat exchanger surfaces624, 632 isolate the disposable heat exchanger member 612 from the heattransfer fluid flowing through the heat transfer paths 634, making theheat exchanger a “dry” heat exchanger in that the heat transfer fluid,e.g., ethylene glycol, does not contact the external surface of thedisposable heat exchanger member 616.

[0482] The disposable heat exchanger member 612 is preferablyconstructed of an IV bag and may include the aforementioned inlet tube626 and outlet tube 628 welded to a bag body 630.

[0483] In use, the heat exchanger 610 is opened by separating the firstheat exchanger mold member 614 and the second heat exchanger mold member616, the disposable heat exchanger member 612 is placed therebetween,and the heat exchanger 610 is closed by bringing the first heatexchanger mold member 614 and the second heat exchanger mold member 616together. When the heat exchanger 610 is closed, the disposable heatexchanger member 612 conforms to the shape of the serpentine grooves636, forming corresponding serpentine fluid passages 638 in thedisposable heat exchanger member 612. As working fluid flows through theserpentine passages 638, heat transferred between the heat transferfluid in the heat transfer paths 634 and heat exchanger surfaces 624,632 causes corresponding heat transfer between the heat exchangersurfaces 624, 632 and the working fluid in the serpentine passages 638.After use, the heat exchanger member 610 is opened by separating thefirst heat exchanger mold member 614 and the second heat exchanger moldmember 616, and the disposable heat exchanger member 610 is disposed ofwith the rest of the disposable components of the circulation set 550.

[0484] Thus, the heat exchanger 610 is a dry heat exchanger because theexternal surface of the disposable heat exchanger member 610 does notcontact a liquid, making it not as messy as the aforementioned coiledheat exchanger 580 that resides in a liquid bath. The heat exchangermember 612 is inexpensive and conveniently disposable after a singleuse.

[0485] In alternative embodiments of the invention, the heat exchangermay have a different construction. For example, a pair of heatexchangers 610 may be stacked on each other in a “double-decker”fashion, sharing a common heat exchanger mold member, the disposableheat exchanger member 610 may include a bag with serpentine orother-shaped passages already formed therein, or the disposable heatexchanger member 610 may be comprised of a stainless steal tube shapedin serpentine or other pattern.

[0486] Temperature and Pressure Sensor Assembly

[0487] With reference to FIGS. 67-70, the temperature and pressuresensor assembly 584 will now be described in more detail. Thetemperature and pressure sensor assembly 584 is used for measuring thetemperature and the pressure of the heat transfer fluid in the supplyline 586 before it enters the catheter 568, and measuring thetemperature and the pressure of the heat transfer fluid in the returnline 588, after it leaves the catheter 568. These measurements areimportant for determining the pressure of the heat transfer fluidflowing through the catheter 568 and the heat transfer that occurs atthe heat transfer element 562 of the catheter 568. Heating or coolingefficiency of the heat transfer element 562 is optimized by maximizingthe pressure or flow rate of working fluid through the catheter.Although the assembly 584 is described as a temperature and pressureassembly, the assembly 584 may be used to measure only temperature orpressure. Further, the assembly 584 may be used for measuring otherphysical characteristics of the working fluid.

[0488] The temperature and pressure sensor assembly 584 includes twomain components, a multi-use, fixed, non-disposable temperature andpressure sensor electronics member 640 and a single-use, disposabletemperature and pressure sensor block member 642.

[0489] With reference to FIGS. 67-68, the temperature and pressuresensor electronics member 640 includes a base 644 and a latch 646pivotally coupled thereto by a pin 648. The base 644 includes an uppersurface 664 and a skirt 666 that together define a receiving area 668for the temperature and pressure block member 642. The base 644 includesfirst and second round pressure transducer holes 670, 672 that receivecorresponding first and second pressure transducers 674, 676 and firstand second round thermocouple holes 678, 680 that receive correspondingfirst and second thermocouples 682, 684. The pressure transducers 674,676 and thermocouples 682, 684 are coupled to electronic circuitry on anundersurface of the base 644. The electronic circuitry is coupled to thecontrol system 548 via appropriate wiring. The base 644 includes asloped surface 650 that terminates in a shoulder portion 652. The latch646 includes a corresponding catch portion 654 that is biased outwardand engages the shoulder portion 652 when the latch 646 is pivoted ontothe base 644. The latch 646 also includes a protruding release member656 that may be manipulated by a user's fingers to disengage the catchportion 654 of the latch 646 from the shoulder portion 652 of the base644.

[0490] With reference to FIGS. 69 and 70, the disposable temperature andpressure sensor block member 642 includes a polycarbonate block or base658 having first and second longitudinally extending lumens or tubes660, 662 extending therethrough. The longitudinally extending lumens660, 662 communicate with corresponding first and second pressuretransducer wells 698, 700 (FIG. 69) and first and second thermocouplewells 702, 704. The pressure transducer wells 698, 700 include centralholes 706 that communicate the respective longitudinally extendinglumens 660, 662, an inner annular raised portion 708, an outer annularrecessed portion 710, and an annular wall 712. The thermocouple wells702, 704 include central holes 714 that communicate with the respectivelongitudinally extending lumens 660, 662, an inner annular recessedportion 716, an outer annular raised portion 718, and an annular wall720.

[0491] Each pressure transducer well 698, 700 includes an O-Ring seal686 fixed on the outer annular recessed portion 710, a pressure sensordiaphragm 688 fixed on the O-Ring seal 686, over the inner annularraised portion 708, and a pressure sensor bushing 690 fixed to theannular wall 712, over the diaphragm 688. Each thermocouple well 702,704 includes an O-Ring seal 692 fixed on the inner annular recessedportion 716, a sensor connection tube 694 fixed on the O-Ring seal 692and extending into the central hole 714, and a temperature sensorbushing 696 fixed to the annular wall 720, over the sensor connectiontube 694.

[0492] The temperature and pressure sensor assembly 584 is assembled byfitting the temperature and pressure block member 642 onto thetemperature and pressure electronics member 640 so that the pressuretransducers 674, 676 and thermocouples 682, 684 of the electronicsmember 640 mate with the corresponding pressure transducer wells 698,700 and thermocouple wells 702, 704 of the block member 642. The latch646 is then pivoted to the locked or engaged position so that the catchportion 654 of the latch 646 engages the shoulder portion 652 of thebase 644. This locks the block member 642 to the electronics member 640.

[0493] After a single use of the circulation set 550 or operation usingthe circulation set 550, the block member 642 is preferably removed fromthe electronics member 640 and disposed of. This is accomplished bydisengaging the catch portion 654 of the latch 646 from the shoulderportion 652 of the base 644 by pulling on the release member 656. Theblock member 642 along with the other disposable components of thecirculation set 550 are then disposed of. Thus, the only reusablecomponent of the pressure and temperature assembly 584 is thetemperature and pressure electronics member 640. The above-describedconstruction and configuration of the block member 642 allows for itsinexpensive manufacture, and thus, disposability, and the reusability ofthe electronics member 640 without contaminating any elements of theelectronics member 640.

[0494] As discussed infra, the air purging mechanism 604 is used toremove air from the lines 586, 588 and lumens 564, 566 of the system544. Removing air from the system 544 maximizes the pressure in thesystem 544, maximizes heat transfer at the heat transfer element 562,and reduces the risk of air entering the blood stream of the patient.The air purging mechanism 604 is employed during a purge phase beforeeach use of the system 544. The purge phase is important foridentification of the type of catheter being used and for earlydetection of problems with the system 544.

[0495] With reference to FIGS. 71 and 72, a method of automaticallyidentifying a catheter connected to the circulation set 550 orautomatically identifying a heat transfer element attached to a catheterthat is connected to a circulation set 550 based on a pressure readingin the circulation set 550 will now be described.

[0496]FIG. 71 is a graph generally illustrating pump motor speed versustime for exemplary purge, idle, and run cycles of the catheter system544. The pump motor speed is representative of the fluid flow ratethrough the system 544. In the purge routine, the fluid flow rate isgradually increased in discrete steps.

[0497] With reference additionally to FIG. 72, each catheter 568 (e.g.,10 F, 14 F, etc.) or heat transfer element 562 connected to a catheter568 has its own unique flow resistance, i.e., pressure versus flowresponse. If during each discrete step of the purge cycle, both theinlet pressure of the catheter 568 and the pump speed are measured, astraight line may be drawn through the measured data points and a slopecomputed. FIG. 72 illustrates such sloped lines for a 10 F catheter anda 14 F catheter attached to the circulation set 550. The catheter 568 orheat transfer element of a catheter 568 used with the circulation set548 may be automatically identified by comparing the computed slope witha list of similarly computed slopes obtained empirically from a set ofavailable catheters. After automatically identifying the catheter beingused, the control system 26 may apply the corresponding optimalparameters for operation of the catheter 568. The computed slope mayalso be used to determine if a problem has occurred in the system 544,e.g., fluid leakage, if the computed slope does not match that of aspecific reference catheter.

[0498] Controlling the Application of Hypothermia

[0499] Background

[0500] So far Innercool has completed over 60 patients for its TCASclinical study in neurosurgery. All of the experimental patients andcontrol were intubated and had an esophageal temperature probe fortemperature monitoring. Monitoring temperature in the distal esophagushas been shown to be extremely reliable for monitoring continually coretemperature, and for providing temperature feedback for controlling theinduction and maintenance of hypothermia.

[0501] As previously mentioned, control algorithms are sometimes used tocontrol the rate at which heat is extracted from the body by thecatheter. These algorithms may be embodied in hardware, software, or acombination of both. The gain factor employed by such algorithms isdependent on the effective thermal mass of the body or organ beingcooled. Thus, it is important to determine the effective thermal mass sothat an appropriate gain factor can be calculated for the feedbackcontrol algorithm.

[0502] The mass of the body (organ or whole body) being cooled can beestimated by relating the power removed by the catheter to the powerlost by the body.

[0503] The power removed by the catheter may be expressed as follows:

P _(catheter) =MC _(f) ΔT  (1)

[0504] Where M is the mass flow rate of the fluid circulating throughthe catheter (typically measured in terms of cc/s), c_(f) is the heatcapacity of the fluid, and AT is the temperature difference between theworking fluid as it enters the catheter and as it exits the catheter.Accordingly, P_(catheter) can be readily calculated by measuring themass flow of the circulating fluid and the temperature differencebetween the working fluid as it enters and exits the catheter.

[0505] The power removed by the catheter as determined by equation (1)may be equated to the power that is lost by the patient's body:

P _(catheter) =mc _(b) ∂T/∂t  (2)

[0506] Where P_(catheter) is now the power lost by the patient's bodyand has the value calculated by equation (1), m is the effective thermalmass of the body being cooled, c_(b) is the heat capacity of the body,and ∂T/∂t is the change in temperature per unit time of the mass beingcooled.

[0507] Accordingly, the effective thermal mass of the body being cooledis:

m=P _(catheter)/(c _(b) ∂T/∂t)  (3)

[0508] Since all the variables in equation (3) are either known or aremeasurable, the effective mass can be determined.

[0509] The mass calculated in this manner is an effective thermal massthat represents the portion of the body from which power is removed(i.e., the portion of the body that is cooled). The temperature changein equation (3) represents the temperature change of the portion of thebody being cooled. For example, if whole body cooling is to beperformed, the change of the core body temperature may be measured tocalculate mass in accordance with equation (3). In general, for wholebody cooling, if the patient is vasoconstricted, the effective mass mayrepresent about 50% of the total body mass. If the patient isvasodilated, the effective mass will be closer to the total body mass.

[0510] Alternatively, if only a selected organ such as the brain is tobe cooled, then the temperature change that will be used in equation (3)would be the temperature change of the organ, assuming of course thatthe organ can be at least briefly considered to be largely thermallyisolated from the remainder of the body. In this case the effective massthat is determined would be comparable to the mass of the organ. If theselected organ to be cooled is the brain, for example, the catheter isplaced in the common carotid artery, the internal carotid artery, orboth. The temperature changed used in equation (3) will be measured byinserting a temperature sensor into the brain or via a tympanic membranesensor, both of which are commercially available.

EXAMPLE

[0511] In an animal study, whole body cooling was accomplished byinserting the catheter through the femoral vein and then through theinferior vena cava as far as the right atrium and the superior venacava. Cooling was initiated by circulating a working fluid at a flowrate of 5 cc/sec. The temperature differential between the fluidentering the catheter and the fluid exiting the catheter was 17° C.Accordingly, the power extracted by the catheter was 354 watts.

[0512] The body core temperature was measured through the esophagus.Twenty minutes after cooling was initiated, the rate at which the coretemperature changed was measured over a period of about ten minutes,resulting in an average temperature change of about 4° C./hr.

[0513] From equation (3) above, the effective thermal mass is:

m=354 watts/(0.965 watts/kg·C.°) (10° C./hr)=37 kg

[0514] The total mass of the animal was 53 kg, and thus the effectivemass was found to be 69% of the total mass.

[0515] Rewarming Strategies According to Procedure

[0516] As noted, certain applications of hypothermia have specifiedrequirements or preferences. Similarly, certain applications ofrewarming have specified requirements or preferences. These aredescribed below.

[0517] Neurosurgery

[0518] In neurosurgery, a typical goal is to rewarm the patient from ahypothermic temperature, such as about 33° C., to a slightly sub-normaltemperature, such as about 35.5° C.(core), in a short time. If therewarm rate is greater than about 2.5° C., this can be achieved in lessthan an hour. As the typical closure time is 60 minutes, this means thatrewarming can occur in the operating room, as can extubation. A neuroexam may then be performed on the conscious patient.

[0519] To accomplish this, the following protocol may be performed. Theprotocol assumes an esophageal temperature probe, although other typesof temperature probes or sensors may also be employed.

[0520] Neurosurgery Protocol

[0521] 1. the patient may be draped, such as by a single or doublelayer.

[0522] 2. The bath temperature, through which the working fluid flows inorder to exchange heat, may be placed at about 50° C. Of course,sufficient temperature drops will occur between this and the bloodtemperature so that the blood temperature does not rise beyond 42° C.

[0523] 3. The target temperature for the control system may beprogrammed at about 35.5° C.

[0524] 4. After achieving target temperature, the patient may be movedto a PACU/ICU and rewarmed using prior art warming techniques, such asconvective air blankets, etc.

[0525] Stroke

[0526] In stroke, a typical goal is to rewarm the patient gradually froma hypothermic temperature, such as about 33° C., to a “normal”temperature, such as about 36.5° C. (core), over an extended period oftime, such as about 12 to 24 hours. The ICP is preferably minimized inits rebound, and patient comfort is maintained, without a shivering orcold sensation.

[0527] To accomplish this, the following protocol may be performed. Theprotocol assumes a bladder temperature probe, although other types oftemperature probes or sensors may also be employed.

[0528] Stroke Protocol

[0529] 1. The patient may be warmed by active surface warming, such asat about 41° C., to prevent shivering. This warming can be provided byelectric blanket or convective air blanket.

[0530] 2. The console may then provide a controlled rewarm to match thetarget temperature ramp function. In other words, a preferred ramp valuemay be input by the caregiver, this ramp being the rate at which thepatient is to be rewarmed. The controller in the console then matchesthe true rate with this programmed ramp. The ramp would be determined bythe amount of time over which the physician wishes the patient'stemperature to rise, as well as the amount of rise needed to reachnormothermia or a pre-normothermia temperature, such as 36.5° C.

[0531] 3. The patient may be administered an anti-shivering drug, suchas meperidine.

[0532] 4. After achieving target temperature, the patient may be movedto a PACU/ICU and rewarmed using prior art warming techniques, such asconvective air blankets, etc.

[0533] Cardiovascular Surgery

[0534] In cardiovascular surgery, a typical goal is to maintainnormothermia in the initial perioperative period following separationfrom cardiopulmonary bypass (CPB) until, e.g., the first 24 hours afterthe operation. In this regime, it would be desirable to rewarm andmaintain the patient's temperature at least about 36° C. in theoperating room during the last 30 to 45 minutes of closing. Complicatingthis is that disconnecting from the CPB pump usually yields an afterdrop of 1 to 2° C. due to redistribution and further heat loss to theenvironment. It is preferred to not have to use active surface warmingduring closure, or in the ICU.

[0535] To accomplish this, the following protocol may be performed. Theprotocol assumes an esophageal temperature probe or that of a PAcatheter, although other types of temperature probes or sensors may alsobe employed.

[0536] Cardiovascular Surgery Protocol

[0537] 1. The heat transfer element and catheter are inserted at thebeginning of the case.

[0538] 2. The CV procedure is performed.

[0539] 3. Once the patient is off the pump, the system is started inrewarming mode and the patient target temperature is set to 36.5° C.

[0540] 4. When desired or appropriate, or after patient reaches thetarget temperature, the catheter may be disconnected from the console inorder to transport patient to the ICU.

[0541] 5. The patient may then be reconnected to the console andrewarming continued, along with prior art warming techniques, such asconvective air blankets, etc.

[0542] 6. Normothermia maintenance may be continued for the next 24hours or for a time period determined by the physician.

[0543] Method of Making the Heat Transfer Element

[0544] The method of manufacturing a heat transfer element will now bedescribed in more detail. The exterior structure of the heat transferelement is of a complex shape as has been described in order to inducemixing in the flow of blood around the heat transfer element, as well asto induce mixing in the flow of working fluid within the heat transferelement. As may be clear, many varieties and shapes may be employed tocause such flow. Such shapes are termed herein as “mixing-inducingshapes”. Examples of mixing-inducing shapes include: helical,alternating helical or other enantiomorphic shapes, aberration-includingshapes, bump-including shapes, channel-including shapes, crenellatedshapes, hook- or horn- shapes, labyrinthine shapes, and any other shapescapable of inducing mixing. Thus, the metallic element or elements orcompounds forming the heat transfer element must be sufficiently ductileto assume such shapes during deposition.

[0545] It is further noted here that while the generic term “deposition”is used, this term is intended broadly to cover any process in whichmetals or coating may be disposed on a mandrel or other layer of a heattransfer element. For example, deposition may include: CVD, PVD,sputtering, MBE, forms of crystal or amorphic material “growth”, spraycoating, electroplating, ECD, and other methods which may be employed toform a mandrel or a coating having a mixing-inducing shape. Methods suchas ECD and electroplating have the benefit of having a chargedworkpiece—this charge may be employed to fix the workpiece to the tool.

[0546] In general, the processes which may be employed to form the heattransfer element include forming a mandrel having a mixing inducingshape, coating the mandrel with a metal layer or a series of layers(i.e., the heat transfer element), and dissolving the mandrel.

[0547] A first step in the process of forming a heat transfer elementmay be to form a mandrel. One type of mandrel may be made of aluminumsuch as Al 6061 with a T6 heat treatment. Aluminum is useful because thesame is capable of being dissolved or leached out easily with a causticsoda. A hole disposed along the axis of the heat transfer element mayspeed such leaching. The mandrel may be formed by machining such as by aCitizen Swiss Screw Machine. The mandrel may also be made via injectionmolding if the same is made of plastic, wax, low-melting-temperaturethermoplastics, and the like. Other methods which may be employed toform the mandrel include machining via laser (note that laser forming istypically only employed for the outside of an element), hydroforming,and other similar methods.

[0548] However the mandrel is formed, it is important for the same tohave a smooth surface finish and exterior texture. In this way, theresulting heat transfer element will be smooth. A smooth mandrel allowsan atraumatic device to be formed around the same. A smooth mandrel alsoallows a smooth metallic coating (heat transfer element) to be simplydeposited around the same thus ensuring uniform heat transfer, aconstant thickness of biocoating, an atraumatic profile, etc.

[0549] A basic series of coating layers is shown in FIG. 73. FIG. 73shows a mechanical layer 724, typically made of a metal, and abiocompatible layer 726. The mechanical layer 724 is the basicconductive element. The mechanical layer 724 is responsible for heatconduction to provide cooling and thus should have a thermalconductivity in the range of about 0.1 to 4 W/cm-K, so long as suchmaterials can be deposited. Typical metals which may be employed for themechanical layer 724 include Ni, Cu, Au, Ag, Ti, Ta, nitinol, stainlesssteel, etc. or combinations of these or other similar elements. Thethickness of the mechanical layer should be less than about 2 mils thickto allow for sufficient flexibility to navigate tortous vasculature,although this is strongly dependent on the type of metal and on thetortuousity of the vasculature involved. Regarding the type of metal,any noble metal may be employed. Certain of these have deleteriousbiocompatibility, however, and each has different manufacturingconcerns. For example, a Au heat transfer element would require a seedlayer since Au will not stick to the Al mandrel.

[0550] Ni has been found to be useful. Cu is also useful and has a highconductivity; unfortunately, Cu is also likely to assume the form of thevasculature in which the same is disposed.

[0551] For sake of argument, it is assumed here that Ni forms the basicheat transfer element. As stated above, Ni is not hemocompatible. Thus,a biocompatible layer 726 is disposed on the mechanical layer 724 as isshown in FIG. 73. The biocompatible layer may be, e.g., urethane,parylene, Teflon®, a lubricious coating, an antithrombogenic coatingsuch as heparin, a noble metal such as Au, or combinations of the aboveor other similar materials.

[0552] One difficulty with the above embodiment may be that, with use ofcertain working fluids, such as saline, corrosion of the mechanicallayer may occur. In the case of a mechanical layer 724 of Ni, saline maybe especially corrosive. Thus, a protective layer 722 may be employedthat is noncorrosive with respect to saline. For example, the protectivelayer 722 may be made of Au. A Au protective layer 722 may encounterdifficulties attaching to an aluminum mandrel, and thus if necessary alayer of Cu may be deposited on the mandrel prior to deposition of theAu layer. Following the dissolution of the mandrel, the Cu layer mayalso be etched away. The protective layer may generally be any noble orinert metal, or may be a polymer or other protective material such asTeflon®.

[0553] Alternatively, the protective layer 722 may be vacuum deposited,such as by a vapor deposition method, following removal or dissolutionof the mandrel. The resulting hole left by the dissolved mandrel allowsa path for vaporized gases or liquid chemicals to flow. Thus, materialscan be deposited in this fashion on the inside of the heat transferelement. The materials so deposited may be the same as those discussedabove: polymers, such as non-corrosive or non-polar polymers, noblemetals, and the like.

[0554]FIG. 74 also shows two layers above the mechanical layer 724: abiocompatible layer 726 and a heparin/lubricious layer 728. These mayalso be combined to form a single biocompatible layer. Alternatively,the biocompatible layer may be a “seed” layer which enhances theconnection of the heparin/lubricious layer 728 to the underlyingmechanical layer 724. Such a seed layer may be, e.g., parylene. Finally,it should be noted that the heparin/lubricious layer 728 is indicated asexemplary only: either heparin or a lubricious layer may be depositedindividually or in combination. For example, in certain applications,heparin may not be necessary.

[0555] Another embodiment is shown in FIG. 75. This embodiment addressesanother difficulty that may occur with various metals. For example, amechanical layer 724 that is made entirely of Ni may have too low aburst pressure, partially due to its porosity. The protective layer 722of FIG. 74 may address some of these concerns. A better approach may bethat shown in FIG. 75. In FIG. 75, the mechanical layer 724 is broken upinto several layers. Two, three, or more layers may be employed. In FIG.75, layers 724 a and 724 c are formed of a first material such as Ni. Aninterior layer 724 b is deposited between layers 724 a and 724 c. Thislayer 724 b may be formed of a second material such as Cu. Thiscombination of layers 724 a, 724 b, and 724 c forms a mechanical“sandwich” structure. The Cu layer 724 b (the second “metal” or “layer”)may serve to close “pinholes” that may exist within the more porous Nilayers 724 a and 724 c (the first “metal” or “layer”).

[0556] One embodiment that has been found useful is that described byTable I below. In Table I, the biocompatible coating is a noble metallayer of Au. It should be noted that Table I describes a very specificembodiment and is provided purely for illustrative purposes. Table Ishould not be construed as limiting. Table I is keyed to FIG. 75. LayerNumber Material Thickness 102 Au (e.g., mil-g- 1/10 mil 45204, type one,grade A, class one) 104a Ni 3 ½/10 to 1 mil 104b Cu 1/10 mil 104c Ni 3½/10 to 1 mil 106 Au 1/10 mil 108 heparin/ 7-10 microns lubricious

[0557] The overall thickness of the group of layers 102-108 may be about1 mil. The nickel and copper may contain traces of other elementswithout deleterious consequences.

[0558] While the particular invention as herein shown and disclosed indetail is fully capable of obtaining the objects and providing theadvantages hereinbefore stated, it is to be understood that thisdisclosure is merely illustrative of the presently preferred embodimentsof the invention and that no limitations are intended other than asdescribed in the appended claims.

1. A method of changing the temperature of a human body, comprising:inserting a catheter having a heat transfer element into a vein of apatient; circulating a working fluid through the catheter and the heattransfer element, the working fluid having a temperature different fromthe patient temperature; administering a therapeutic amount ofmeperidine, whereby shivering is lessened.
 2. The method of claim 1,further comprising circulating a working fluid through the catheter andthe heat transfer element, the working fluid having a temperature higherthan the patient temperature.
 3. The method of claim 1, furthercomprising circulating a working fluid through the catheter and the heattransfer element, the working fluid having a temperature lower than thepatient temperature.
 4. A method of changing the temperature of a humanbody, comprising: inserting a catheter having a heat transfer elementinto a vein of a patient; circulating a working fluid through thecatheter and the heat transfer element, the working fluid having atemperature different from the patient temperature; administering atherapeutic amount of a prodine, whereby shivering is lessened.
 5. Themethod of claim 4, further comprising circulating a working fluidthrough the catheter and the heat transfer element, the working fluidhaving a temperature higher than the patient temperature.
 6. The methodof claim 4, further comprising circulating a working fluid through thecatheter and the heat transfer element, the working fluid having atemperature lower than the patient temperature.
 7. A method of changingthe temperature of a human body, comprising: inserting a catheter havinga heat transfer element into a vein of a patient; circulating a workingfluid through the catheter and the heat transfer element, the workingfluid having a temperature different from the patient temperature;administering a therapeutic amount of fentanyl, whereby shivering islessened.
 8. The method of claim 7, further comprising circulating aworking fluid through the catheter and the heat transfer element, theworking fluid having a temperature higher than the patient temperature.9. The method of claim 7, further comprising circulating a working fluidthrough the catheter and the heat transfer element, the working fluidhaving a temperature lower than the patient temperature.
 10. A method ofchanging the temperature of a human body, comprising: inserting acatheter having a heat transfer element into a vein of a patient;circulating a working fluid through the catheter and the heat transferelement, the working fluid having a temperature different from thepatient temperature; administering a therapeutic amount of an opioid,whereby shivering is lessened.
 11. The method of claim 10, furthercomprising circulating a working fluid through the catheter and the heattransfer element, the working fluid having a temperature higher than thepatient temperature.
 12. The method of claim 10, further comprisingcirculating a working fluid through the catheter and the heat transferelement, the working fluid having a temperature lower than the patienttemperature.
 13. A method of changing the temperature of a human body,comprising: inserting a catheter having a heat transfer element into avein of a patient; circulating a working fluid through the catheter andthe heat transfer element, the working fluid having a temperaturedifferent from the patient temperature; administering a therapeuticamount of a drug selected from the group consisting essentially ofprodine, fentanyl, and an opioid, in combination with a delta opiatereceptor antagonist, whereby shivering is lessened.
 14. The method ofclaim 13, further comprising circulating a working fluid through thecatheter and the heat transfer element, the working fluid having atemperature higher than the patient temperature.
 15. The method of claim13, further comprising circulating a working fluid through the catheterand the heat transfer element, the working fluid having a temperaturelower than the patient temperature.
 16. The method of claim 13, whereinthe antagonist is naltrindole or naltriben.
 17. A method of changing thetemperature of a human body, comprising: inserting a catheter having aheat transfer element into a vein of a patient; circulating a workingfluid through the catheter and the heat transfer element, the workingfluid having a temperature different from the patient temperature;administering a therapeutic amount of a (+) isomer of a prodine in whicha hydroxyl has been added to the phenyl ring, whereby shivering islessened.
 18. The method of claim 17, wherein the hydroxyl is added inthe m position.
 19. The method of claim 17, wherein the prodine isalpha-allylprodine, and the 3-methyl is replaced with an allyl group.20. A method of changing the temperature of a human body, comprising:inserting a catheter having a heat transfer element into a vein of apatient; circulating a working fluid through the catheter and the heattransfer element, the working fluid having a temperature different fromthe patient temperature; administering a therapeutic amount of a (+)beta isomer of a prodine in which the 3-methyl group is replaced with ann-propyl or allyl group, whereby shivering is lessened.
 21. A method ofchanging the temperature of a human body, comprising: inserting acatheter having a heat transfer element into a vein of a patient;circulating a working fluid through the catheter and the heat transferelement, the working fluid having a temperature different from thepatient temperature; administering a therapeutic amount of a isomer of acis-picenadol.
 22. The method of claim 21, wherein the isomer is the (−)enantiomer.
 23. The method of claim 21, further comprising administeringa therapeutic amount of a racemic mixture of isomers of a cis-picenadol.24. A method of changing the temperature of a human body, comprising:inserting a catheter having a heat transfer element into a vein of apatient; circulating a working fluid through the catheter and the heattransfer element, the working fluid having a temperature different fromthe patient temperature; administering a therapeutic amount of a isomerof tramadol.
 25. The method of claim 1, further comprising administeringa therapeutic amount of buspirone.
 26. A method of changing thetemperature of a human body, comprising: inserting a catheter having aheat transfer element into a vein of a patient; circulating a workingfluid through the catheter and the heat transfer element, the workingfluid having a temperature different from the patient temperature;administering a therapeutic amount of a isomer of nefopam.
 27. Themethod of claim 26, wherein the isomer is the (−) enantiomer.
 28. Themethod of claim 26, further comprising administering a therapeuticamount of a drug selected from the group consisting essentially of aprodine, meperidine, thorazine, buspirone, clonidine, and tramadol, andcombinations thereof.